Indole-derived arylpiperazines as ligands for 5HT1 -like, 5HT1B and 5HT1D receptors

ABSTRACT

Novel indole-derived azylpiperazines of general formula (I), wherein, inter alia, R 1  is NH 2  or NO 2 , R&#39; 1 , R 2 , R&#39; 2 , R 3  and R 4  are H, Z is --C-- and X is 0. Methods for preparing such derivatives and the therapeutical uses thereof are also disclosed.

The present application is a U.S. national application filed under 35 USC 371 of PCT/FR94/01343, filed Nov. 17, 1994, which in turn is based upon the priority of French application 9313875, filed Nov. 19, 1993.

The present invention relates to new indole-derived arylpiperazines, to processes for their preparation and to their therapeutic uses.

The compounds according to the present invention are ligands having a very high affinity and a very good selectivity for the receptors commonly known as 5HT₁ -like receptors and more particularly for the receptors known as 5HT_(1B) and 5HT_(1D) receptors, according to the new nomenclature recently proposed by P. Humphrey, P. Hartig and D. Hoyer (TIPS, 14, 233-236, 1993).

Medicaments including (alone or in association with other therapeutic agents) the active principles of the present invention are employed in the treatment, both curative and preventive, of diseases related to dysfunctioning of 5HT_(1-like) receptors, including 5HT_(1B), 5HT_(1D)α and 5HT_(1D)β receptors, to their deregulation or to modifications in the activity of the endogenous ligand (generally serotonin).

It has moreover been demonstrated that serotonin could play a role in certain diseases such as depression, pain, obsessional convulsive disorders, panic attacks, obesity, schizophrenia, anxiety, certain sexual disfunctionings or alternatively certain forms of degeneration such as Parkinson's or Alzheimer's disease refer, for example, to: S. Langer, N. Brunello, G. Racagni and J. Mendlecvicz, "Serotonin receptors subtypes: pharmacological significance and clinical implications", edited by Karger (1992), B. E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992), D. G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, Suppl. 4, 6-13 (1992), E. Zifa and G. Fillion, Pharmacological Reviews, 44, 401-458 (1992), and R. W. Fuller, J. Clin. Psychiatry, 53, 36-45 (1992)!.

The compounds of the present invention are powerful and selective ligands of 5HT_(1-like) receptors which can act as agonists, partial agonists or antagonists as regards these receptors and can therefore be applied in the disorders related to serotonin mentioned above.

The majority of the compounds of the present invention are in addition powerful (as regards their affinity and as regards their intrinsic activity or effectiveness) and selective agonists of 5HT_(1B) and 5HT_(1D) receptors. Agonists of 5HT_(1-like) receptors and more particularly of 5HT_(1D) receptors have a selective vasoconstrictive activity and are used in the treatment of migraine and vasospastic disorders (see, for example, A. Doenicke et al., The Lancet, 1, 1309-1311 (1988), M. D. Ferrari and P. R. Saxena, Cephalalgia, 13, 151-165 (1993), S. J. Peroutka, Headache, 30, 5-11 (1990), M. A. Moskowitz, TIPS, 13, 307-311 (1992), W. Feniuk, P. P. Humphrey, M. S. Perren, H. E. Connor and E. T. Whalley, J. Neurol., 238, S57-S61 (1991) and A. V. Deligonis and S. J. Peroutka, Headache, 31, 228-231 (1991)!.

The compounds of the present invention, which are, for the most part, powerful and selective agonists of 5HT_(1-like) receptors, are therefore more particularly employed in the curative and prophylactic treatment of "classic" (with aura) and "common" (without aura) migraine attacks, facial vascular pain, chronic vascular cephalalgias and vasospastic disorders.

The prior state of the art in this field is illustrated in particular by

French Patent Applications F 9215919 (30/12/92) and F 9307982 (30/6/93), which describe new indole compounds derived respectively from piperazines and from arylamines as ligands of 5HT_(1B) -5HT_(1D) receptors.

Patent Application FR 2,671,971, which describes 5-O-carboxymethylated derivatives of tryptamine which have a good affinity for 5HT_(1D) receptors.

European Patent Applications 0,313,397, 0,486,666, 0,494,774-A1, 0,497,512-A2, 0,501,568-A1, 0,464,558 and 0,548,813-A1 and Patent Application WO 92/13856, which describe heterocyclic derivatives derived from tryptamine as agonists of 5HT_(1-like) receptors.

European Patent Applications 0,533,266, 0,533,267 and 0,533,268, which claim benzamides derived from arylpiperazine as antagonists of the 5HT_(1D) receptor.

Nevertheless, these patent applications do not in any case describe or suggest the indolic piperazine derivatives which form part of the present invention: the present invention describes a new class of indole-derived arylpiperazines which is distinguished from the closest derivatives of the prior art (and in particular from French Patent Application F 9215919, filed on 30/12/92) not only by their novel and different chemical structure but also by their biological profile and their therapeutic potential, since many compounds according to the present invention have the advantage of combining, for the first time in the same molecule, a very strong affinity for 5HT_(1B) or 5HT_(1D) receptors, a high selectivity with respect to 5HT_(1A) receptors and a notable agonist effectiveness (intrinsic activity).

The present invention relates to compounds of formula I: ##STR2## to their preparation and to the medicaments containing them.

In the formula (I),

R₁ represents an NH₂, NO₂, NH--NH₂, NH--OH, NCOR₇ (OH), NR₅ R₆, NHCOR₇, NHCONR₅ R₇, NHSO₂ R₇, NHCO₂ R₇, SO₂ R₇, SO₂ NHR₇, NHCH₂ SR₇, NHCH₂ S(O)R₇, NHCH₂ SO₂ R₇, CN, NHCONH₂, SO₂ NH₂, N(SO₂ R₇)₂, CH₂ NR₅ R₆, CH₂ NHCOR₇, CH₂ NHCONR₅ R₆, CH₂ NHSO₂ R₇, CH₂ NHCO₂ R₇ or OSO₂ R₇ radical which can be in the o, m or p position on the aromatic ring.

R'₁ represents one or a number of substituents which can be in various positions on the aromatic ring, such as H, methyl, ethyl, propyl, isopropyl, n-buryl, s-butyl, t-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, cycloalkyl, OH, SR₅, OR₅ or a halogen (chlorine, fluorine, bromine or iodine), or alternatively R'₁ can be identical to R₁.

Z represents C=O, C=S, SO₂, (CH₂)_(n) or alternatively --CO(CH₂)_(n) -- in which n is between 1 and 5.

R₂ and R'₂, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical or a phenyl, benzyl, cycloalkyl or arylalkyl radical which are optionally substituted by one or a number of substituents chosen from halogen atoms or alkyl, aryl, acycl, alkoxy and alkylthio radicals.

X represents CH₂ or O or the R₁ R'₁ group represents a C--C double bond.

R₃ represents a hydrogen atom, a linear or branched alkyl radical or a phenyl, alkyl, aryl, COR₇, CO₂ R₇, CONHR₇ or SO₂ R₇ radical.

R₄ represents a hydrogen, chlorine, fluorine or bromine atom or a linear or branched alkyl radical.

R₅ and R₆, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl or t-butyl, or an arylalkyl radical, such as a benzyl or a phenethyl.

R₇ represents a linear or branched alkyl radical comprising from 1 to 5 carbon atoms, a trifluoromethyl or 2,2,2-trifluoroethyl, an aryl radical (such as phenyl), a heterocycle (such as a 5-membered heterocycle containing one or a number of sulfur, oxygen or nitrogen atoms) or an arylalkyl (such as a benzyl or a phenethyl) in which the aromatic ring may be variously substituted in various positions by alkyl (methyl, ethyl, propyl or butyl), trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, thiol, ether (OCH₃, OC₂ H₅ or OCH(Me)₂), thioether (SCH₃ or SC₂ H₅), halogen (chlorine, fluorine, bromine or iodine), nitrile, acetyl, carbonyl (COR₅), carboxyl (CO₂ R₅), nitro (NO₂), amine (NRSR₆), NHSO₂ R₅, NHCO₂ R₅, NHCOR₅, NHCONR₅ R₆ or NHSO₂ NR₅ R₆ residues.

their salts, solyates and bioprecursors which are acceptable in therapeutic use.

In the preceding definitions and those which will be cited below, except when otherwise mentioned, the alkyl, alkoxy or alkylthio radicals contain 1 to 6 straight- or branched-chain carbon atoms and the cycloalkyl portions contain 3 to 7 carbon atoms. In the formula (I), the halogen atoms are preferably chlorine, fluorine or bromine atoms.

The compounds of formula (I) containing one or a number of asymmetric centers have isomer forms.

The racemates and the pure enantiomers of these compounds also form part of this invention.

The invention also comprises the salts, solyates (for example hydrates) and bioprecursors of these compounds which are acceptable in therapeutic use.

Mention will be made, among the salts which are acceptable in therapeutic use of the indoles of general formula (I), of the salts formed by addition with organic or inorganic acids and for example the hydrochlorides, the hydrobromides, the sulfates, the fumarates and the maleares. Other salts may be useful in the preparation of the compounds of formula (I), for example adducts with creatinine sulfate.

The expression "bioprecursors" as used in the present invention applies to compounds in which the structure differs from that of the compounds of formula (I) but which, administered to an animal or to a human being, are converted in the body to a compound of formula (I).

A valuable class of compounds according to the invention comprises those which correspond to the general formula (Ia) ##STR3## in which R₁, R'₁, Z, X, R₅ and R₆ are defined as above in the formula (I), and their salts, solyates (for example hydrates) and bioprecursors which are acceptable in therapeutic use.

The invention also comprises the preparation, by the processes described below, of the compounds of general formula (I) and of their salts, solyates (such as hydrates) or bioprecursors which are acceptable in therapeutic use.

Generally, the compounds of general formula (I) in which R₆ represents a hydrogen are prepared from derivatives of formula (II) ##STR4## in which R'₁, R₁, Z, R₂, R'₂, X, R₃, R₄ and R₅ are described as above and R'₆ represents a COR₈ or CO₂ R₈ group, preferably CO₂ R₈ in which R₈ is preferably a t-butyl or benzyl residue. Conversion of the compounds of formula (II) in which R'₆ is a CO₂ ^(t) Bu (BOC) group to compounds of formula (I) in which R₆ is a hydrogen is preferably carried out using an acid, such as trifluoroacetic acid or hydrochloric acid, in an organic solvent, such as ether, tetrahydrofuran, toluene, dichloromethane, chloroform, methanol, ethanol or isopropanol, at a temperature of between -15° C. and 40° C. Conversion of the compounds of formula (II) in which R'₆ is a CO₂ CH₂ C₆ H₅ (commonly called Z) group to a compound of formula (I) in which R₆ is a hydrogen is preferably carried out by catalytic hydrogenation, using for example palladium-on-charcoal as catalyst, under atmospheric hydrogen pressure, in a solvent, such as THF, ethanol, isopropanol or ethyl acetate, which can contain up to 10% of acetic or citric acid, at a temperature of between 0° and 60° C. In the following definitions, the expression "R₆ described as above" should be regarded as implying that R₆ can also represent R'₆.

The preparation of the derivatives of formula (I) in which R'₁, R₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above and X represents an oxygen atom are prepared, generally, by condensation of a derivative of general formula (III) ##STR5## in which R₁, R'₁, Z, R₂ and R'₂ are defined as in the formula (I) and L represents a leaving group, such as a halogen (preferably a bromine, iodine or chlorine atom) or an O-mesylate, O-triflate or O-tosylate, with a derivative of serotonin of general formula (IV): ##STR6## in which the R₃, R₄, R₅ and R₆ residues are described as above.

The preparation of the derivatives of formula (I) by condensation of the derivatives of formula (III) with the derivatives of formula (IV) can be carried out, generally, in the presence of an organic base (NaH, KH, Et₃ N, DBU, DBN, TMP, DIPEA, t-BuOK) or an inorganic base (K₂ CO₃, KHCO₃, NaHCO₃, CS₂ CO₃, KOH, NaOH, CaCO₃ and the like), in an anhydrous solvent, such as THF, DMF, DMSO, acetone, diethyl ketone, methyl ethyl ketone, acetonitrile or DME, at a temperature of between 20° and 140° C., in the present or in the absence of a salt as catalyst which may be KI, Bu₄ NI, LiI, AgBF₄, AgCIO₄, Ag₂ CO₃, KF, Bu₄ NF or CsF. The choice of the experimental conditions for carrying out the condensation between the derivatives of formula (III) and (IV) in order to obtain the derivatives of formula (I) is very clearly dependent on the nature of the substituents in the reactants (III) and (IV) and more particularly on the nature of the Z, R₂ and R'₂ groups. By way of example, when Z is a carbonyl (CO) functional group, R₂ is a hydrogen atom and X a halogen, condensation between (III) and (IV) to give (I) is preferably carried out at 80° C., in methyl ethyl ketone, in the presence of an excess of K₂ CO₃ and of a catalytic amount of KI. When Z is a carbonyl group and when R₂ and R'₂ are both other than a hydrogen, the preferred method comprises the reaction of a derivative of formula (IV) with this derivative of formula (III), in the presence of a silver salt such as silver tetrafluoroborate and of an inorganic base such as K₂ CO₃. When the Z group is defined as (CH₂)_(n), condensation between the (III) and (IV) derivatives is carried out in a solvent such as DMF or DMSO, in the presence of a base such as DBU or DIPEA, at 100° C., in the presence of a catalytic amount of Bu₄ NI or of KI. An alternative method comprises the condensation of the (III) and (IV) derivatives, under neutral conditions, in DMF, in the presence of a large excess of a fluoride such as KF, CsF or Bu₄ NF.

The compounds of general formula (III) in which the R₁, R'₁, R₂, R'₂ and L substituents are defined as above are prepared by methods which differ according to the nature of the Z residue. Thus, the derivatives of formula (III) in which Z is a carbonyl group forming part of an amide functional group are obtained by reaction of the piperazines of general formula (V). ##STR7## in which the R₁ and R'₁ residues are defined as in the formula (I), with a derivative of formula (VI) ##STR8## in which R₂ and R'₂ are defined as in the formula (I) and Z represents C=0. This reaction, which makes possible the preparation of the derivatives of formula (III) in which Z=CO and X=Cl from the arylamines (V) and the acid chlorides (VI), is a well known reaction for the formation of amides from an amine and from an acid chloride and can be carried out in a solvent such as dichloromethane, THF, chloroform, acetone, methyl ethyl ketone, DME or acetonitrile, at a temperature of between -20° C. and 80° C., in the presence of a base, such as a tertiary amine (DBU, Et₃ N or DIPEA) or inorganic bases, such as carbonates (KHCO₃, NaHCO₃, K₂ CO₂, Na₂ CO₃ or Cs₂ CO₃), sodium hydroxide or alternatively potassium hydroxide.

The derivatives of formula (III) in which Z represents a --(CH₂)_(n) -- group are generally prepared by condensation of an arylamine of formula (V) with a derivative of formula (VII) ##STR9## in which L represents a leaving group, such as a chlorine, a bromine, an iodine or a mesylate, tosylate or triflate group, R₂ and R'₂ are defined as in the formula (I) and L' can be either identical to L or represents an OR' group in which R' is defined as a protective group for an alcohol, such as a silyl ether (SiMe₃, Si^(t) BuMe₂ or SiC₆ H₅ Me₂), a tetrahydropyran or alternatively a benzyl or a trityl. It is clearly understood that, in the case where L' is other than L, condensation between the piperazine of formula (V) and the intermediate (VII) is followed by hydrolysis of the OR' protective group in order to give anintermediate alcohol derivative which is converted to a leaving group which results in the compounds (III) in which R₁, R'₁, R₂, R'₂ and L are defined as above. In the procedure mentioned above, hydrolysis of the OR' functional group to an alcohol is carried out by the described and appropriate methods according to the nature of R' (with reference to the work by T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1981) and the conversion of the alcohol thus obtained to the leaving group (so as to obtain the compounds (III)! is carried out by techniques and methods which are well known for this type of conversion, such as the use of SOCl₂ or POCl₃ in dichloromethane for the formation of derivatives of formula (III) in which L=Cl, the use of PBr₃ or Br₂ PPh₃ for the formation of derivatives of formula (III) in which L=Br, the use of PI₃ or P₂ I₄ for the formation of derivatives of formula (III) in which L=I, the use of tosyl chloride for the formation of derivatives of formula (III) in which L=OTos, the use of mesyl chloride for the formation of derivatives of formula (III) in which L=OMes and finally the use of triflic anhydride for the formation of derivatives of formula (III) in which L=OTf.

The derivatives of formula (III) in which Z=SO₂ are generally prepared by reaction of the piperazine derivatives of general formula (V), in which the R₁ and R'₁ groups are defined as in the general formula (I), with a derivative of formula (VI) in which R₂ and R'₂ are defined as in the formula (I) and Z represents SO₂.

The compounds of general formula (I) can also be prepared by another process which comprises the treatment of an arylpiperazine of general formula (V) defined as above with a derivative of serotonin of general formula (VIII. ##STR10## in which the R₂, R'₂, R₃, R₄, R₅ and R₆ residues are defined as described above in the formula (I) and L is defined as a leaving group, such as a halogen (preferably a bromine, iodine or chlorine atom), a mesylate, a rosylate or a triflate, or the precursor of a leaving group, such as a hydroxyl radical.

The preparation of the derivatives of formula (I) in which Z represents a --(CH₂)_(n) -- residue by this process is carried out by condensation between a piperazine derivative of formula (V) and an intermediate of general formula (VIII) in the presence of an organic base (NaH, ^(t) BuOK, DBU or DIPEA) or an inorganic base (KOH, K₂ CO₃, NaHCO₃ or Cs₂ CO₃) in an anhydrous solvent, such as THF, DMF, DMSO, acetonitrile or methylethyl ketone, at a temperature of between 20° and 100° C.

The intermediates of formula (VIII) can be prepared by condensation of a derivative of serotonin of formula (IV) ##STR11## in which R₃, R₄, R₅ and R₆ are defined as in the formula (I), with a derivative of formula (IX) ##STR12## in which L' and L" can be simultaneously halogens (chlorine, bromine or iodine) if R₂ and R'₂ represent a hydrogen atom; in the other cases, L' represents an OR group where R is a conventional protective group, such as a silyl (trimethylsilyl, triethylsilyl or ^(t) butyldimethylsilyl), benzyl, tetrahydropyranyl or trityl group, and in this case L" represents a leaving group, such as a halogen (preferably a chlorine, an iodine or a bromine), an OMes, an OTos or an OTf. In this case, after condensation, L', which represents OR, will be deprotected and converted to the leaving group L as defined in the formula (VIII) by the methods described above.

This condensation reaction between the intermediates (IV) and (IX) as described above is carried out in basic medium (in the present of a base, such as NaH, KH, ^(t) BuOK, K₂ CO₃, Cs₂ CO₃, DIPEA or DBU) in an anhydrous solvent, such as DMSO, DMF, THF, acetonitrile, methyl ethyl ketone or DME, at a temperature of between 0° and 100° C.

In the specific case of the derivatives of formula (I) in which R₁, R'₁, R₃, R₄, R₅ and R₆ are described as above but where Z represents --(CH₂)--, a preferred method of synthesis comprises the reduction of the corresponding derivatives of formula (I) in which Z represents CO by a reducing agent which makes possible the conversion of an amide to an amine, such as borane (BH₃.Me₂ S) or LiAlH₄, use being made of the methods and techniques which are well known for this type of reduction.

In the case of the derivatives of formula (I) in which R₁, R'₁, Z, R₂, R'₂, R₃, R₄, R₅ and R₆ are described as above and in which X=CH₂, a general method of synthesis comprises the condensation of an intermediate of general formula (X) ##STR13## in which L is a leaving group defined as above and Z, R₂, R'₂, R₃, R₄, R₅ and R₆ are described as above, with an arylpiperazine of general formula (V) in which R₁ and R'₁ are defined as above. The methods used for obtaining the products of general formula (I) in which X=CH₂ by condensation of the intermediates (X) and (V) vary according to the nature of the Z residue and may be comparable, according to the variation in Z, to the methods described previously for the synthesis of the products (III) by condensation of the intermediates (V) and (VI).

The indole derivatives of general formula (X) in which Z=CO, L is a leaving group such as a halogen, R₂, R₃, R₄, R₅ and R₆ are described as above and R'₂ is a hydrogen can be obtained by condensation of a 5-bromoindole derivative of formula (XI) ##STR14## in which R₃, R₄, R₅ and R₆ are defined as above, with an acid or an ester derived from this unsaturated acid of general formula (XII) ##STR15## in which the R₂ residue is defined as above, use being made of a palladium (o) catalysis according to the method for the alkylation of aromatics well known as the Heck reaction, followed by reduction of the double bond by catalytic hydrogenation (atmospheric H₂, Pd/C, methanol) and by conversion of the acid or of the ester thus formed to the derivative X by methods and techniques which are well known to the person skilled in the art for the conversion of a carboxylic acid or of a corresponding ester to the acid chloride X (L=Cl, Z=CO) or to an activated ester capable of being condensed with an amine in order to form an amide (in particular by intermediate formation of a mixed anhydride with ethyl chloroformate).

The derivatives of general formula (I) in which R₁, R'₁, R₂, R₃, R₄, R₅ and R₆ are described as above, Z=X=CH₂ and R'₂ =H are prepared from the products of general formula (I) in which R₁, R'₁, R₂, R₃, R₄, R₅ and R₆ are described as above, Z=CO, X=CH₂ and R'₂ =H by reduction of the amide functional group with a reducing agent well known for this type of reaction, such as lithium aluminum hydride, in an aprotic solvent, such as ether or THF.

The derivatives of general formula (I) in which R₁, R'₁, R₂, R₃, R₄, R₅ and R₆ are described as above, Z=SO₂, X=CH₂ and R'₂ =H are prepared by the Heck condensation from an intermediate of formula (XI) with an unsaturated sulfonamide of formula (XIII) ##STR16## in a solvent such as triethylamine in the presence of a phosphine such as tri(O-tolylphosphine) at a temperature of between 60° and 100° C.

The methods for the preparation of derivatives of formula (I) from other derivatives of formula (I) in which at least one of the R₁, R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ or R₆ substituents are different, by techniques and methods well known to the person skilled in the art, must also be regarded as an integral part of this invention.

In particular, the present invention also claims a method for the preparation of numerous compounds of general formula (I), in which R₁ is an NH₂, NH--NH₂, NHOH, NR₅ R₆, NHCOR₇, NHCONR₅ R₇, NHSO₂ R₇ or NHCO₂ R₇ radical in the ortho, meta or para position, from compounds of general formula (Ib) prepared as described above and in which R₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above. ##STR17##

Thus, the compounds of general formula (Ic), in which R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above ##STR18## are prepared by reduction of the nitro group by methods and techniques well known for this type of reduction (with reference, for example, to: R. C. Larouk "Comprehensive Organic Transformation", p. 412 (1989), VCH.), such as atmospheric hydrogenation catalyzed by paladium-on-charcoal, the use of SnCl₂ or of zinc or alternatively of rhodium catalyst in the presence of hydrazine.

This last method additionally makes it possible to control the reduction of the nitro group and also to isolate the intermediate hydroxylamine of general formula (Id), which also forms part of this invention. ##STR19##

The synthetic intermediates of general formula (Ie), in which R₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above ##STR20## can also be prepared from the anilines of structure Ic, after reaction with nitrous acid (HNO₂), by using methods and techniques well known for this type of conversion (cf. Patai, "The Chemistry of Diazonium and Diazo Groups", Wiley, N.Y., 1978).

These intermediates (Ie) make it possible to prepare the products of general formula (Ia), in which R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above but in which R₁ =SO₂ NHR₇, after reaction with SO₂ in the presence of cupric chloride (Gilbert, Synthesis, 1-10, 1969), followed by condensation of the intermediate sulfonyl chloride with an amine (R₇ NH₂) in the presence of a base, such as pyridine, triethylamine or DMAP.

The intermediates (Ie) also make it possible to prepare the products of general formula (Ia), in which R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above but in which R₁ =NH--NH₂, after reduction of the diazonium group, in particular by using sodium sulfite (Na₂ SO₃) (Huisgen and Lux, Chem. Bet. 93, 540, 1960).

The compounds of general formula (I), in which the R₁ group represents NR₅ R₆, NHCOR₇, NHCONR₅ R₇, NHSO₂ R₇, NHCO₂ R₇ in the ortho, meta or para position, can also be obtained from the compounds of formula (Ic) in which R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above by various reactants and methods which depend on the nature of the R₁ group. Thus, the compounds of formula (I) in which R₁ represents an NR₅ R₆ group (in which R₆ =H or R₅) are prepared by reaction in a basic medium (in the presence of an organic base, such as DBU, ^(t) BuOK, DMAP or DIPEA, or an inorganic base, such as CS₂ CO₃, HaH or KH) of the intermediate (Ic) with corresponding alkylating agents (R₅ --L in which L represents a chlorine, bromine or iodine atom or an O-mesyl, O-toxyl or O-trifluorasulfonyl radical). Control of the reaction (time, solvent, temperature or number of equivalents of R₅ --L) makes it possible to obtain the mono- or dialkylated aniline.

The compounds of general formula (I) in which R₁ represents NHCOR₇ are also prepared by reaction of the corresponding anilines of formula (Ic) after reaction with an acylating agent, such as an acid chloride (ClCOR₇) or an anhydride (R₇ CO)₂ O!, in the presence of a base, such as triethylamine, pyridine or DMAP, in a polar aprotic solvent, such as DMF or dichloromethane.

The compounds of formula (I) in which R₁ represents NHCOOR₇ are also accessible by a similar reaction in which the amine of formula (Ic) is condensed with a chloroformate of structure ClCOOR₇.

The compounds of formula (I) in which R₁ represents NHSO₂ R₇ are themselves also accessible by a similar reaction which comprises the condensation of the aniline of formula (Ic) with a sulfonyl chloride of formula ClSO₂ R₇.

The compounds of formula (I) in which R₁ represents NHCONR₅ R₇ can also be obtained from the corresponding aniline (Ic) by different methods. Thus, the amines of general formula (Ic) can be converted beforehand to isocyanates of formula (I) in which R₁ represents N=C=O (cf. Patai, "The Chemistry of Cyanates and Their Thio Derivatives, pt. 2, Wiley, N.Y., 1977; pp 619-818 and 1003-1221), followed by the addition reaction of an amine of formula HNR₅ --R₇ in the presence of a base such as Et₃ N. Alternatively, the compounds of formula (I) in which R₁ =NHCONR₅ R₇ can also be prepared by condensation of the aniline of formula (Ic) with an intermediate of formula ClCONR₅ R₇ in the presence of a base, such as ET₃ N or DMAP, in a polar aprotic solvent, such as CH₂ CL₂ or DMF.

The derivatives of general formula (I) in which R₁, R'₁, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above and Z represents C=S are obtained by reaction of the compounds of general formula (I), in which R₁, R'₁, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above and Z represents C=O, with Lawesson's reagent 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide!in toluene.

The derivatives of general formula (I) in which R₁, R'₁, Z, R₂, R'₂, X, R₃, R₄, R₅ and R₆ are described as above and in which R₃ represents a hydrogen can be converted to derivatives of formula (I) in which R₃ represents an alkyl, benzyl, COR₇, CO₂ R₇, CONHR₇ or SO₂ R₇ radical by reaction in basic medium with, respectively, an alkyl halide, a benzyl halide, an acid chloride, a chloroformate, a chloroformamide or a sulfonyl chloride by methods and techniques well known for this type of reaction and which, by way of example, are described in "The Chemistry of Indoles", edited by R. S. Sundberg, vol. 18 of "Organic Chemistry, A Series of Monographs", Academic Press, NY, 1970.

It will be understood that, in some of the above conversions, it may be necessary or desirable to protect possible sensitive groups of the molecule in question in order to avoid undesirable side reactions. This can be carried out by the use of conventional protective groups such as those described in "Protective Groups in Organic Synthesis", edited by J. F. McOwie, Plenum Press, 1973 and in T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1981. The protective groups can be removed during any suitable subsequent stage, by using methods and techniques also described in the references cited above. Thus, in some specific cases, it may be necessary to protect the indole nitrogen during the preparation of compounds of formula (I) in which R₃ represents a hydrogen.

When it is desired to isolate a compound according to the invention in the salt form, for example in the form of a salt formed by addition with an acid, this can be done by treating the free base of general formula (I) with an appropriate acid, preferably in an equivalent amount, or with creatinine sulfate, in an appropriate solvent.

When the processes described above for preparing the compounds of the invention give mixtures of stereoisomers, these isomers can be separated by conventional methods, such as preparative chromatography.

When the new compounds of general formula (I) have one or a number of asymmetric centers, it can be prepared in the form of a racemic mixture or in the form of enantiomers, whether by enantioselective synthesis or by resolution. The compounds of formula (I) having at least one asymmetric center can, for example, be separated into their enantiomers by the usual techniques, such as the formation of diastereomeric pairs by formation of a salt with an optically active acid, such as (-)-di-p-toluoyl-1-tartaric acid, (+)-di-p-toluoyl-1-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, (+)-phenylpropionic acid or (-)-phenylpropionic acid, followed by fractional crystallization and regeneration of the free base. The compounds of formula (I) in which R₆ is a hydrogen comprising at least one asymmetric center can also be resolved by formation of diastereomeric amides which are separated by chromatography and hydrolyzed in order to release the chiral auxiliary.

Generally, the compounds of formula (I) can be purified by the usual methods, for example by crystallization (in particular when the compounds of formula (I) are isolated in the salt form), chromatography or extraction.

The examples which follow illustrate the invention without, however, limiting the scope thereof.

EXAMPLE 1 2- 3-(2-Aminoethyl)-1-H-indol-5-yloxy!-1-( 4-nitrophenyl)piperazin-1-yl!ethanone hydrochloride ##STR21## 1A: 3-(2-N-tert-butoxycarbonyl)aminoethyl)-1-H-indol-5-ol

The creatine sulfate monohydrate salt of serotonin (102 g, 252 mmol) is treated with di-tert-butyl dicarbonate (82.6 g, 378 mmol) in water (2.1 l) in the presence of 2N sodium hydroxide (420 ml) at room temperature. After 1 hour, the reaction mixture is diluted with ethyl acetate (3 l) and stirred for 10 minutes. The two phases formed are separated by settling; the organic phase is washed with water, dried over sodium sulfate, filtered and then evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol (20/1, v/v) mixture. The pure compound is isolated in the form of a brown syrup (65.9 g, 95%). Elemental analysis (C₁₅ H₂₀ N₂ O₃), % calculated: C 65.20, H 7.30, N 10.14, % found: C 64.15, H 7.47, N 9.77.

Proton nuclear maguetic resonance spectrum, CDCl₃ (ppm): 1.44 s, 9H (t-Bu); 2.86 t, 2H (CH₂); 3.45 m, 2H (CH₂); 4.68 s, 1H (NH); 5.59 s, 1H (O--H); 6.77-7.26 m, 4H (Ar+ethylenic); 7.99 s, 1H (NH).

1B: 2-chloro-1- 4-nitrophenyl)piperazin-1-yl!ethanone

(4-Nitrophenyl)piperazine (7 g, 33.8 mmol) in solution in methyl ethyl ketone (223 ml), in the presence of calcium carbonate (10.1 g; 101.4 mmol), is treated at 0° C. and dropwise with chloroacetyl chloride (3.2 ml; 40.5 mmol). After 1 hour at 0° C., the reaction mixture is diluted with ethyl acetate, filtered through celite and washed with water and then with a sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The brown solid obtained (7.8 g, 82%) is used without additional purification in the following stage.

1C: 2- 3-(2-N-(tert-butoxycarbonyl)aminoethyl)-1-H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone.

A mixture of the compound 1A (9.67 g, 35.01 mmol) and of the compound 1B (24.8 g, 87.5 mmol) in methyl ethyl ketone (400 ml), in the presence of potassium carbonate (12.1 g, 87.5 mmol) and of potassium iodide (581 mg; 3.5 mmol), is heated at reflux for 5 hours. The compound 1A (2.0 g, 7.2 mmol) is again added and the reaction mixture is stirred at reflux for an additional 1 hour. The mixture is then diluted with dichloromethane, filtered through celite and washed with water and then with a sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and then evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (3/1, v/v) mixture. The pure product is obtained in the form of an orange powder (18.2 g, 83%).

Elemental analysis (C₂₇ H₃₃ N₅ O₆), % calculated: C 61.94, H 6.35, N 13.38, % found: C 61.19, H 6.22, N 13.02.

Proton nuclear magnetic resonance spectrum, CDCl₃ (ppm):

1.44 s, 9H (t-Bu); 3.86 t, 4H (CH₂); 3.83 m, 4H (CH₂); 4.65 s, 1H (NH); 4.79 s, 2H (COCH₂ O); 6.79-7.30 m, 6H (Ar+ethylenic); 8.11-8.16 m, 3H (Ar+NH). Melting point: 198° C.

1: 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone hydrochloride.

The product 1C (930 mg, 1.77 mmol) in solution in toluene (46 ml) is treated with trifluoroacetic acid (10 ml). After 1 h 30 at room temperature, the mixture is diluted with dichloromethane and washed with 2N sodium hydroxide and then with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatoraphed on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is obtained in the form of a yellow syrup (317 mg, 45%). This compound is diluted in methanol and the bishydrochloride is formed by addition of the necessary amount of hydrochloric acid in methanol.

Elemental analysis (C₂₂ H₂₇ N₅ O₄ Cl₂), % calculated: C 53.23, H 5.48, N 14.11, % found: C 53.83, H 5.77, N 13.80.

1H nuclear magnetic resonance spectrum, d6-DMSO (ppm):

2.99 s, 4H (CH₂); 3.54-3.71 m, 8H (CH₂), 4.84 s, 2H (COCH₂ O); 6.77-6.83 dd, 1H (ethylenic); 7.01-7.29 m, 5H (Ar); 8.06-8.11 m, 5H (Ar+NH₃ ⁺); 10.85 d, 1H (NH). Melting point: 206° C.

EXAMPLE 2 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(aminopheryl)piperazin-1-yl!ethanone hydrochloride ##STR22##

The product 1 (5 g, 9.5 mmol), in suspension in methanol (250 ml) in the presence of a catalytic amount of palladium-on-charcoal (505 mg, 0.47 mmol), is hydrogenated in a Parr apparatus, under a pressure of 40 psi. After 12 hours, the mixture is filtered through celite and the latter is washed a number of times with methanol, which makes it possible to obtain the virtually pure reduction product in the filtrate. The celite is then washed with dichloromethane, which makes it possible to recover the unreacted starting material.

The filtrate containing the product formed is evaporated to dryness and the syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane acetone (3/1, v/v) mixture. The pure product is obtained in the form of a yellow syrup (2.8 g, 60%).

1H nuclear magnetic resonance spectrum, CDCl₃ (ppm): 1.44

s, 9H (t-Bu); 2.18 s, 2H (NH₂); 2.87-3.80 m, 12H (CH₂); 4.66 s, 1H (NH); 4.77 s, 2H (COCH₂ O); 6.63-7.28 m, 8H (Ar+ethylenic); 8.16 s, 1H (NH).

2: 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-aminophenyl)piperazin-1- yl!ethanone hydrochloride

The product 2A (252 mg, 0.51 mmol), in solution in toluene (13 ml) is treated with trifluoroacetic acid (3 ml) at room temperature. After 1 hour, the mixture is diluted with ethyl acetate and washed with 2N sodium hydroxide, with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The syrup obtained is chromatographed on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a yellow syrup (174 mg, 87%). The compound obtained is dissolved in methanol and the hydrochloride is formed by addition of the necessary amount of hydrochloric acid in methanol.

Elemental analysis (C₂₂ H₃₀ N₅ O₂ Cl₃.2H₂ O), % calculated: C 49.03, H 6.36, N 12.99, % found: C 49.37, H 6.18, N 12.67.

1H nuclear magnetic resonance spectrum, d6-DMSO (ppm):

2.99-3.70 m, 12H (CH₂); 4.83 s, 2H (COCH₂ O); 6.76-6.82 dd, 1H (ethylenic); 7.05-7.28 m, 7H (Ar); 8.13 s, 3H (NH₃ ⁺); 10.86 s, 1H (NH). Melting point: 196° C.

EXAMPLE 3 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!acetamide hydrochloride ##STR23##

The product 2A (300 mg, 0.61 mmol), in solution in pyridine (7.5 ml), is treated at 0° C. with acetic anhydride (60 ml, 0.61 mmol). After stirring for 2 hours at room temperature, the mixture is diluted with ethyl acetate and washed successively with a saturated copper sulfate solution, water and finally with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (2/1, v/v) mixture. The pure product is obtained in the form of a yellow syrup (249 mg; 77%). This compound is then deprotected according to the method described for the preparation of Example 2.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in methanol, in the compound 3 (113 mg, 36%).

Elemental analysis (C₂₄ H₃₁ N₅ O₃ Cl₂.0.5H₂ O), % calculated: C 55.71, H 6.23, N 13.53, % found: C 55.70%, H 6.40, N 13.46.

1H nuclear magnetic resonance spectrum, d6-DMSO (ppm):

2.00 s, 3H (CH₃); 2.76-3.16 m, 8H (CH₂); 3.68 m, 6H (CH₂ +H₂ O); 4.82 s, 2H (COCH₂ O); 6.77-6.82 dd, 1H (ethylenic); 6.97-7.50 m, 7H (Ar); 8.01 s, 3H (NH₃ ⁺); 9.85 s, 1H (NH); 10.86 s, 1H (NH). Melting point: 169° C.

EXAMPLE 4 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!benzamide hydrochloride ##STR24##

The compound 4 is obtained from the product 2A (700 mg, 1.42 mmol) and benzoyl chloride (0.16 ml, 1.42 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in methanol, in the compound 4 (560 mg, 66%).

Elemental analysis (C₂₉ H₃₃ N₅ O₃ Cl₂.2H₂ O), % calculated: C 57.43, H 6.15, N 11.55; % found: C 57.32, H 5.97, N 11.53.

1H NMR, d6-DMSO (ppm): 3.00 s, 4H (CH₂); 3.35-3.42 d, 4H (CH₂); 3.89 s, 4H (CH₂); 4.87 s, 2H (COCH₂ O); 6.78-6.84 dd, 1H (ethylenic); 7.21-7.99 m, 12H (Ar); 8.10 s, 3H (NH₃ ⁺); 10.35 s, 1H (NH); 10.86 s, 1H (NH). Melting point: 184°-185° C.

EXAMPLE 5 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!methanesulfonamide hydrochloride ##STR25##

The compound 5 is obtained from the product 2A (201 mg, 0.407 mmol) and mehanesulfonic chloride (31 μl; 0.407 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in methanol, in the compound 5 (151 mg, 66%).

Elemental analysis (C₂₃ H₃₁ N₅ O₅ SCl₂.2H₂ O), % calculated: C 49.11, H 5.91, N 12.45; % found: C 49.88, H 5.73, N 11.97.

1H NMR, d6-DMSO (ppm): 2.89 s, 3H (MeSO₂); 2.99-3.19 m, 8H (CH₂); 3.68 s, 4H (CH₂); 4.82 s, 2H (COCH₂ O); 6.77-6.82 dd, 1H (ethylenic); 7.01-7.29 m, 7H (Ar); 8.02 s, 3H (NH₃ ⁺); 9.41 s, 1H (NH); 10.85 s, 1H (NH). Melting point: 150° C.

EXAMPLE 6 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!(methanesulfonyl)methanesulfonamide hydrochloride ##STR26##

The product 2A (500 mg, 1.01 mmol), in solution in dichloromethane (12.5 ml) in the presence of triethylamine (0.56 ml, 4.04 mmol), is treated with mesyl chloride (0.17 ml, 2.03 mmol) at 0° C. After leaving overnight at room temperature, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with an ethyl acetate/dichloromethane (2/1, v/v) mixture. The pure product is obtained in the form of a colorless syrup (127 mg, 20%).

This compound is then deprotected according to the method described for the preparation of Example 2.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in mathenol, in the compound 6 (109 mg, 90%).

Elemental analysis (C₂₄ H₃₃ N₅ O₆ S₂ Cl₂), % calculated: C 46.30, H 5.34, N 11.25; % found: C 46.47, H 5.47, N 10.96.

1HNMR, d6-DMSO (ppm): 2.99-3.90 m, 18H (MeSO₂ --+CH₂); 4.83 s, 2H (COCH₂ O); 6.78-6.83 dd, 1H (ethylenic); 6.97-7.33 m, 7H (Ar); 7.96 s, 3H (NH₃ ⁺); 10.85 s, 1H (NH). Melting point: 202° C.

EXAMPLE 7 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!ethanesulfonamide hydrochloride ##STR27##

The compound 7 is obtained from product 2A (800 mg; 1.6 mmol) and ethanesulfonic chloride (0.15 ml, 1.6 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure product is isolated in the form of an orange syrup which results, after treatment with hydrochloric acid in methanol, in the compound 7 (730 mg, 78%).

Elemental analysis (C₂₄ H₃₃ N₅ O₄ S₁ Cl₂.H₂ O), % calculated: C 50.00, H 5.95, N 12.54; % found: C 50.00, H 5.75, N 12.54.

1H NMR, d6-DMSO (ppm): 1.15-1.22 t, 3H (CH₃); 2.94-3.16 m, 10H (CH₂); 3.73 m, 4H (CH₂); 4.82 s, 2H (COCH₂ O); 6.77-6.82 dd, 1H (ethylenic); 7.13-7.28 m, 7H (Ar); 7.99 s, 3H (NH₃ ⁺); 9.55 s, 1H (NH); 10.84 s 1H (NH). Melting point: 222° C.

EXAMPLE 8 Thiophene-2-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide hydrochloride ##STR28##

The compound 8 is obtained from the product 2A (800 mg, 1.62 =mmol) and thiophene sulfonic chloride (296 mg, 1.62 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/15, v/v) mixture. The pure product is isolated in the form of a yellow powder which results, after treatment with hydrochloric acid in methanol, in the compound 8 (575 mg, 57%).

Elemental analysis (C₂₆ H₃₁ N₅ O₄ S₂ Cl₂.H₂ O), % calculated: C 49.52, H 5.27, N 11.11; % found: C 50.44, H 5.49, N 10.86.

1H NMR, d6-DMSO (ppm): 2.99-3.16 m, 8H (CH₂); 3.67 s, 4H (CH₂), 4.81 s, 2H (COCH₂ O); 6.76-6.81 dd, 1H (ethylenic indole); 7.00-7.28 m, 8H (Ar +ethylenic thiophene); 7.48 dd, 1H (ethylenic thiophene); 7.88 dd, 1H (ethylenic thiophene); 8.06 s, 3H (NH₃ ⁺); 10.13 s, 1H (NH); 10.86 s, 1H (NH).

Melting point: 185° C.

EXAMPLE 9 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yl-oxy!acetyl}piperazin-1-yl)phenyl!(thiophene-2-sulfonyl)-thiophene-2-sulfonamide hydrochloride ##STR29##

The compound 9 is obtained from the product 2A (800 mg, 1.62 mmol) and thiophene sulfonic chloride (335 mg, 1.94 mmol) according to the procedure described for the preparation of Example 6.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/6.5/15, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in methanol, in the compound 2 (380 mg, 32%).

Elemental analysis (C₃₀ H₃₃ N₅ O₆ S₄ Cl₂), % calculated: C 7.49, H 4.35, N 9.23; % found: C 47.62 H 4.40, N 9.20 H NMR, d6-DMSO (ppm): 3.00 s, 4H (CH₂); 3.27 s, 4H (CH₂), 3.63 s, 4H (CH₂); 4.82 s, 2H (COCH₂ O); 6.77-7.30 m, 10H, (Ar+ethylenic); 7.70 d, 2H (ethylenic); 8.05 s, 3H (NH₃ ⁺); 8.20 d, 2H (ethylenic); 10.85 s, 1H (NH).

Melting point: 180° C.

EXAMPLE 10 3,5-Dimethylisoxazole-4-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!sulfonamide hydrochloride ##STR30##

The compound 10 is obtained from the product 2A (800 mg, 1.62 mmol) and 3,5-dimmethylisoxazole-4-sulfonic chloride (317 mg, 1.62 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 10 (576 mg, 55%).

Elemental analysis (C₂₇ H₃₄ N₆ O₅ S₁ Cl₂ ; H₂ O), % calculated: C 50.11, H 5.67, N 12.99; % found: C 50.21, H 5.22, N 12.52.

1H NMR, d6-DMSO (ppm): 2.15 s, 3H (Me); 2.33 s, 3H (Me), 2.92-3.07 m, 8H (CH₂); 3.64 s, 4H (CH₂); 4.80 s, 3H (COCH₂ O); 6.77-6.82 dd, 1H (ethylchic); 6.95-7.28 m, 7H (Ar); 7.88 s, 3H (NH₃ ⁺); 9.98 s, 1H (NH); 10.84 s, 1H (NH).

Melting point: 193° C.

EXAMPLE 11 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-N-{ethoxycarbonyl}aminophenyl)piperazin-1-yl!-ethanone hydrochloride ##STR31##

The compound 11 is obtained from the product 2A (600 mg, 1.21 mmol) and ethyl chloroformate (0.13 ml, 1.33 mmol) according to the procedure described for the preparation of Example 6.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 11 (230 mg, 38%).

Elemental analysis (C₂₅ H₃₂ N₅ O₄ Cl), % calculated: C 59.81; H 6.42, N 13.95; % found: C 60.26, H 6.52, N 13.49.

1H NMR, d6-DMSO (ppm): 1.22 t, 3H (CH₃); 2.81-3.03 m, 8H (CH₂); 3.64 s, 4H (CH₂); 4.03-4.14 q, 2H (CH₂); 4.80 s, 2H (COCH₂ O); 6.75-6.80 dd, 1H (ethylchic); 6.80-7.33 m, 7H (Ar); 9.34 s, 1H (NH); 10.74 s, 1H (NH).

Melting point: 153° C.

EXAMPLE 12 2,2,2-Trifluoroethane 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-sulfonamide hydrochloride ##STR32##

The compound 12 is obtained from the product 2A (800 mg, 1.62 mmol) and trifluoroethane sulfonic chloride (0.36 ml, 3.24 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is obtained in the form of a green-yellow syrup which results, after treatment with hydrochloric acid in methanol, in the compound 12 (643 mg, 65%).

1H NMR, d6-DMSO (ppm): 2.99-3.16 m, 8H (CH₂); 3.67 s, 4H (CH₂), 4.82 s, 2H (COCH₂ O); 6.76-6.82 dd, 1H (ethylenic); 6.99-7.55 m, 7H (Ar); 7.55 s, 2H (CF₃ CH₂ SO₂); 8.07 s, 3H (NH₃ ⁺); 10.12 s, 1H (NH); 10.85 s, 1H (NH).

EXAMPLE 13 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!isopropanesulfonamide hydrochloride ##STR33##

The compound 13 is obtained from the product 2A (800 mg, 1.62 mmol) and isopropylsulfonic chloride (0.18 ml, 1.62 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 13 (381 mg, 41%).

1H NMR, d6-DMSO (ppm): 11.22 d, 6H (Me); 2.99-3.17 m, 9H (CH₂ +CH); 3.73 m, 4H (CH₂); 4.83 s, 2H (COCO₂ O); 6.78-7.03 dd, 1H (ethylenic); 7.16-7.28 m, 7H (Ar); 8.07 s, 3H (NH₃ ⁺); 9.59 s, 1H (NH); 10.86 s, 1H (NH).

EXAMPLE 14 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-nitrophenyl)piperazin-1-yl)ethanone hydrochloride ##STR34##

The compound 14 is obtained from (2-nitrophenyl)piperazine (15 g, 72.5 mmol), chloroacetyl chloride (5.78 ml, 72.56 mmol) and the compound 1A (10.9 g, 39.6 mmol) according to the procedure described for the preparation of Example 1.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 14 (22 g, 67%).

Elemental analysis (C₂₂ H₂₆ N₅ O₄ Cl.13H₂ O), % calculated: C 54.67, H 5.96, N 14.49, Cl 7.33; % found: C 54.63, H 5.74, N 14.25, Cl 7.65.

1H NMR, d6-DMSO. (ppm): 3.00 m, 8H (CH₂); 3.63 s, 4H (CH₂), 4.81 s, 2H (COCH₂ O); 6.78-6.83 dd, 1H (ethylenic); 7.15-7.87 m, 7H (Ar); 8.00s, 3H (NH₃ ⁺); 10.85 s, 1H (NH).

Melting point: 130° C.

EXAMPLE 15 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl)ethanethione hydrochloride ##STR35##

The compound 1, in the base form (600 mg, 1.42 mmol), in solution in toluene (12 ml) in the presence of Lawesson's reagent (401 mg, 0.99 mmol), is heated at reflux for 3 hours. The mixture is brought back to room temperature, diluted with dichloromethane and washed with water (twice). The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatoraphed on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 15 (378 mg, 52%).

EXAMPLE 16 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(hydroxyamino)phenyl)piperazin-1-yl)ethanone hydrochloride ##STR36##

The compound 1C, (5 g, 9.54 mmol), in solution in THF (120 ml) in the presence of a catalytic amount of Rhodium-on-alumina (490 mg, 0.48 mmol), is treated at 0° C. with hydrazine hydrate (1.16 ml, 23.8 mmol). The mixture is stirred at room temperature for 4 hours and the catalyst is then filtered off on celite; the mixture is diluted with dichloromethane and washed with water. The organic phase is dried with sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (5/1 and then 2/1, v/v) mixture. The pure product is obtained in the form of a green-yellow syrup.

This product is then deprotected according to the method described for the preparation of Example 2.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (90/9.5/0.5, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 16 (780 mg, 21%).

EXAMPLE 17 2-{5- 4-(4-Nitrophenylpiperazine-1-sulfonylmethoxy!-1H-indol-3-yl}ethylamine hydrochloride ##STR37##

The compound 17 is obtained from (4-nitrophenyl)piperazine (1 g, 4.82 mmol), chloromethanesulfonyl chloride (719 mg, 4.82 mmol) and the compound 1A (739 mg, 2.63 mmol) according to the procedure described for the preparation of Example 1. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 17 (420 mg, 30%).

EXAMPLE 18 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!propane-1-one hydrochloride ##STR38##

The compound 18 is obtained from (4-nitrophenyl)piperazine (1 g, 4.82 mmol), α-methylchloroacetyl chloride (0.46 ml, 4.82 mmol) and the compound 1A (739 mg, 2.63 mmol) according to the procedure described for the preparation of Example 1. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 18 (470 mg, 35%).

EXAMPLE 19 2- 3-(2-(Dimethylamino)ethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone hydrochloride ##STR39##

The compound 19 is obtained from (4-nitrophenyl)piperazine (200 mg, 0.96 mmol), chloroacetyl chloride (76 ml, 0.96 mmol) and bufotenine (108 mg, 0.53 mmol) according to the procedure described for the preparation of Example 1. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 19 (69 mg, 25%).

EXAMPLE 20 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(dimethylamino)phenyl)piperazin-1-yl!ethanone hydrochloride ##STR40##

The product 2A (800 mg, 1.62 mmol), in solution in tetrahydrofuran (27 ml) in the presence of tetrabutylammonium bromide (157 mg, 0.486 mmol) and of sodium hydroxide solution (6N) (2.7 ml, 16.2 mmol), is treated with dimethyl sulfate (0.61 ml, 6.48 mmol). After stirring for 2 h 30 at room temperature, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

The syrup obtained is chromatoraphed on a column of silica gel eluted with a dichloromethane/acetone (4/1, v/v) mixture.

This product is then deprotected according to the method described for the preparation of Example 2.

The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 20 (344 mg, 40%).

EXAMPLE 21 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yl-oxy!acetyl}piperazin-1-yl)phenyl!benzenesulfonamide hydrochloride ##STR41##

The compound 21 is obtained from the product 2A (800 mg, 1.62 mmol) and benzenesulfonic chloride (0.21 ml, 1.62 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 21 (450 mg, 47%).

Elemental analysis: (C₂₈ H₃₂ N₅ O₄ SCl.1.2H₂ O), % calculated: C 56.83, H 5.86, N 11.84; % found: C 56.66, H 5.56, N 11.67.

1H NMR, d6-DMSO (ppm): 2.98-3.02 m, 8H (CH₂); 3.60 m, 4H (CH₂); 4.79s, 2H (COCH₂ O); 6.75-7.72 m, 13 H (Ar+ethylenic); 7.99 s, 3H (NH3⁺); 9.90 s, 1H (NH); 10.84 s, 1H (NH).

Melting point: 263° C.

EXAMPLE 22 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-methoxy-4-nitrophenyl)piperazin-1-yl!ethanone hydrochloride ##STR42##

The compound 22 is obtained from (2-methoxy-4-nitrophenyl)piperazine (1.64 g, 6.92 mmol), chloroacetyl chloride (0.55 ml, 6.92 mmol) and the compound 1A (1.06 g, 3.8 mmol) according to the procedure described for the preparation of Example 1. Purification of the product in the base form is carried out by chromatoraphy on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 22 (747 mg, 71%).

Elemental analysis 1H NMR, d6-DMSO (ppm):

EXAMPLE 23 2-(5-{2- 4-(4-Nitrophenyl)piperazin-1-yl!-ethoxy}-1H-indol-3-yl)ethylamine hydrochloride ##STR43## EXAMPLE 23A 2- 5-(2-Chloroethoxy)-1H-indol-3-yl!-N-(tert-butoxycarbonyl)aminoethyl

The product 1A (5 g, 18.09 mmol), in solution in methyl ethyl ketone (25 ml) in the presence of potassium carbonate (15 g, 108.5 mmol), is treated with 1-bromo-2-chloroethane. After 24 hours at reflux, the mixture is diluted with dichloromethane, filtered through celite and evaporated to dryness. The brown syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (30/1, v/v) mixture. The pure product is obtained in the form of white crystals (5.2 g, 84%).

Elemental analysis (C₁₇ H₂₃ N₂ O₃ Cl), % calculated: C 60.26, H 6.84, N 8.27; % found: C 60.37, H 6.98, N 8.21.

1H NMR, CDCl₃ (ppm): 1.46 s, 9H (t-Bu); 2.88-2.95 t, 2H (CH₂); 3.45 m, 2H (CH₂); 3.81-3.87 t, 2H (CH₂); 4.26-4.32 t, 2H (CH₂); 4.65 s, 1H (NH); 6.87-6.93 dd, 1H (ethylenic); 7.01-7.29 m, 3H (Ar); 8.16 s, 1H (NH).

Melting point: 129° C.

EXAMPLE 23B 2-(5-{2- 4-(4-Aminophenyl)piperazin-1-yl!-ethox}-1H-indol-3-yl)ethylamine hydrochloride

A mixture of the product 23A (1.03 g, 3.07 mmol) and (4-nitrophenyl)piperazine (636 mg, 3.07 mmol) in dimethylformamide (1.5 ml) in the presence of potassium carbonate (1.27 g, 9.3 mmol) and potassium iodide (166 mg, 0.3 mmol) is heated at 80° C. for 31 hours. The mixture is then diluted with ethyl acetate and washed with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The yellow solid obtained is purified on a column of silica gel eluted with a dichloromethane/methanol (30/1, v/v) mixture. The pure product is isolated in the form of a yellow solid (1.46 g, 94%).

This product is deprotected according to the method described for the preparation of Example 2. The product is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture.

The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 23 (1.17 g, 78%).

Elemental analysis (C₂₂ H₂₉ N₅ O₃ Cl₂.1.5H₂ O), % calculated: C 51.87, H 6.33, N 13.75; % found: C 52.41, H 6.18, N 13.68.

1H NMR, d6-DMSO (ppm): 3.01-3.58 m, 12H (CH₂); 4.19 m, 2H (CH₂); 4.48 m, 2H (CH₂); 6.79-6.84 dd, 1H (ethylenic); 7.11-7.31 m, 5H (Ar); 8.09-8.13 m, 5H (Ar+NH₃ ⁺); 10.91 s, 1H (NH); 11.74 s, 1H (NH⁺).

Melting point: 148° C.

EXAMPLE 24 3- 3-(2-aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!prop-2-en-1-one hydrochloride ##STR44## EXAMPLE 24A 2-(5-bromo-1H-indol-3-yl)-N-(tert-butoxycarbonyl)ethylamine

5-Bromotryptamine (43 g, 180 mmol), in solution in tetrahydrofuran (500 ml) in the presence of sodium hydroxide solution (2N) (260 ml), is treated with di-tert-butyl dicarbonate (60 g, 275 mmol) at room temperature.

After stirring overnight at room temperature, the mixture is diluted with ethyl acetate and washed with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a toluene/ethyl acetate (80/20, v/v) mixture. The pure product is obtained in the form of a syrup which crystallizes from petroleum ether to give a beige powder (27 g, 44%).

Melting point: 103° C.

EXAMPLE 24B Methyl 3- 3-(2-(N-tert-butoxycarbonylamino)ethyl)-1H-indol-5-yl!acrylate

The product 24A (5 g, 14.7 mmol) is heated in the presence of methyl acrylate (2 ml, 22.1 mmol), trethylamine (10 ml), tri-o-tolylphosphine (90 mg, 0.29 mmol) and palladium acetate (33 mg, 1.47 mmol) at 100° C. in a long narrow cylindrical bottle with a screw top. After stirring overnight, the same amounts of tri-o-tolylphosphine and palladium acetate are added. After 5 hours, the mixture is diluted with ethyl acetate and the precipitate formed is filtered off on celite. The filtrate is washed with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (15/1 then 10/1, v/v) mixture. The pure product is obtained in the form of a pale yellow syrup (4.36 g, 86%).

Elemental analysis (C₁₉ H₂₄ N₂ O₄), % calculated: C 66.26, H 7.02, N 8.13; % found: C 65.40, H 6.74, N 7.79.

1H NMR, CDCl₃ (ppm): 1.44 s, 9H (t-Bu); 2.92-2.99 m, 2H (CH₂); 3.45-3.48 m, 2H (CH₂); 3.82 s, 3H (COOMe); 4.64 s, 1H (NH); 6.39-6.47 d, 1H (ethylenic); 7.05-7.89 m, 5H (Ar+ethylenics); 8.31 s, 1H (NH).

EXAMPLE 24C 3- 3-(2-N-{tert-butoxycarbonyl}aminoethyl)-1H-indol-5-yl!acrylic acid

The product 24B (2 g, 5.80 mmol), in solution in ethanol (20 ml) and water (0.2 ml), is treated with potassium hydroxide pellets (650 mg, 11.6 mmol). After 3 hours at reflux, the mixture is diluted with ethyl acetate and washed with a normal hydrochloric acid solution, with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product 24C is obtained pure in the form of a white powder (1.85 g, 97%).

Melting point: 179°-181° C.

EXAMPLE 24 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!prop-2-en-1-one hydrochloride

The product 24C (500 mg, 1.51 mmol), in solution in anhydrous dichloromethane (18 ml) in the presence of N-methylmorpholine ( illegible! ml, 1.66 mmol), is treated at -15° C., under nitrogen, with ethyl chloroformate (0.16 ml, 1.66 mmol). After stirring for 15 minutes at -10° C., (4-nitrophenyl)piperazine (781 mg, 3.77 mmol) is added and the mixture is stirred from -10° C. to room temperature for 1 hour. The mixture is then diluted with dichloromethane and washed with a saturated sodium bicarbonate solution, with water and then with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol (40/1, v/v) mixture. The pure product is isolated in the form of a syrup (564 mg, 72%). This product is then deprotected according to the method described for the preparation of Example 2.

The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 24 (277 mg, 50%).

EXAMPLE 25 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!propan-1-one hydrochloride ##STR45## EXAMPLE 25A 3- 3-(2-N-{tert-butoxycarbonyl}aminoethyl)-1H-indol-5-yl!proplonic acid

The product 24C (500 mg, 1.51 mmol), in solution in methanol (4 ml) in the presence of a catalytic amount of palladium-on-charcoal (30 mg), is hydrogenated by hydrogen gas. After 1 h 30 at room temperature, the mixture is diluted with dichloromethane, filtered through celite and evaporated to dryness. The pure product is obtained by recrystallization from ether to give a beige powder (483 mg, 96%).

Elemental analysis (C₁₈ H₂₄ N₂ O₄), % calculated: C 65.04, H 7.28, N 8.43: % found: C 64.57, H 7.35, N 8.25.

1H NMR, d6-DMSO (ppm): 1.38 s, 9H (t-Bu); 2.50-3.40 m, 8H (CH₂); 6.87-7.32 m, 4H (Ar +ethylenic); 10.68 s, 1H (NH); 12.05 s, 1H (NH).

EXAMPLE 25 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!propan-1-one hydrochloride

The compound 25 is obtained from the compound 25A (640 mg, 1.92 mmol) and 4-nitrophenylpiperazine (981 mg, 4.73 mmol) according to the method described for the preparation of Example 24 from 24C. The pure product is obtained in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 25 (531 mg, 56%).

Elemental analysis (C₂₃ H₂₉ Cl₂ N₅ O₃.1.7H₂ O), % calculated: C 52.62, H 6.22, N 13.34, Cl 13.50; % found: C 52.56, H 5.93, N 13.16, Cl 14.72.

1H NMR, d6-DMSO (ppm): 2.69 m, 2H; 2.88-3.00 m, 6H; 3.42 m, 4H; 3.60 broad s, 4H; 6.94-7.42 m, 6H; 8.05 d, 2H; 8.14 s, 3H; 10.88 s, 1H.

Melting point: 145° C.

EXAMPLE 26 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide hydrochloride ##STR46## Method A

The compound 26 is obtained from the product 2A (768 mg, 1.55 mmol) and 4-nitrobenzenesulfonyl chloride (689 mg, 3.10 mmol) according to the procedure described for the preparation of Example 3.

Purification of the product, in the base form, is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 26 (391 mg, 44%).

Elemental analysis (C₂₈ H₃₂ N₆ O₆ S₁ --2.5H₂ O), % calculated: C 48.28, H 5.35, N 12.06, Cl 10.18, % found: C 48.09, H 5.05, N 11.84, Cl 9.85.

1H NMR, d6-DMSO (ppm): 2.96-3.14 m, 8H; 3.62 m, 4H; 4.78 s, 2H; 6.73-6.79 dd, 1H; 6.95-7.26 m, 7H; 7.89-7.94 m, 5H; 8.33-8.37 d, 2H; 10.31 s, 1H; 10.83 s, 1H.

Melting point: 190° C.

Mass spectrum (DCI/NH₃): m/z 579 (M+H).

Method B 26A-4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenylamine

1-(4-Nitrophenyl)piperazine (50 g, 241.2 mmol), in solution in dichloromethane (11) in the presence of triethylamine (50.3 ml, 361.8 mmol), is treated with di-tert-butyl dicarbonate (63.2 g, 289.4 mmol) at room temperature for 1 hour. The mixture is then diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

The crude product obtained is taken up in methanol and is hydrogenated at atmospheric pressure in the presence of a catalytic amount of (5%) palladium-on-charcoal (2 g, 0.94 mmol).

After stirring for 28 h at room temperature, the mixture is filtered through celite and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a hexane/ethyl acetate (1/1, v/v) mixture. The pure product is isolated in the form of a pale pink powder (57 g, 85%).

Elemental analysis (C₁₅ H₂₅ N₃ O₂), % calculated: C 64.95, H 8.35, N 15.14; % found: C 64.95, H 8.31, N 14.89.

1H NMR, d6-DMSO (ppm): 1.42 s, 9H; 2.83 t, 4H; 3.42 t, 4H; 4.62 s, 2H; 6.49 d, 2H; 6.70 d, 2H.

Melting point: 96° C.

26B--N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-nitrobenzenesulfonamide

The compound 26A (37.6 g, 135.5 mmol), in a solution of dichloromethane (1 l) in the presence of triethylamine (20.7 ml, 149.1 mmol), is treated at 0° C. with 4-nitrobenzenesulfonyl chloride (30.04 g, 135.5 mmol). After stirring for 3h 30 from 0° C. to room temperature, 4-nitrobenzenesulfonyl chloride (9.1 g; 40.6 mmol) is again added. After 2 h 30, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The dark green syrup obtained is taken up in methanol while hot and then cooled in order to obtain crystallization of the expected product, which is isolated by filtration on a buchner and washing with ether. A yellow powder (50 g, 80%) is obtained, which powder is used straight away in the following reaction.

26C--4-Nitro-N-(4-(piperazin-1-yl)phenyl)benzenesulfonamide

The above product (50 g, 108.1 mmol), in solution in toluene (1.3 l), is treated at room temperature with trifluoroacetic acid (180 ml). After 3 h 30, the mixture is evaporated to dryness and coevaporated 5 times with toluene. The syrup obtained is purified on a silica column eluted with a dichloromethane/methanol/aqueous ammonia (90/9.5/0.5, v/v) and then (85/14/1, v/v) mixture. The product 26C and isolated in the form of a pale yellow powder (29 g, 75%).

1H NMR, d6-DMSO (ppm): 3.20 m, 8H; 6.88 m, 4H; 7.93 d, 2H; 8.37 d, 2H; 9.29 s, 1H.

Melting point: 240° C.

26D--N- 4-(4-{2- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide

3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetic acid (1 g, 2.99 mmol), prepared according to a method described above (Patent Application FR 2699918-A), in solution in anhydrous dichloromethane (50 ml) in the presence of N-methylmorpholine (0.45 ml, 4.5 mmol), is treated at -15° C. and under nitrogen with ethyl chloroformate (0.37 ml, 3.9 mmol).

After stirring for 30 minutes, the compound 26C (2.2 g, 6.0 mmol) is added and the mixture is stirred from -15° C. to room temperature for 4 hours. The mixture is diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, then with water and finally with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (2/1 then 1/1, v/v) mixture. The product 26D is isolated in the form of a pale yellow powder (1.3 g, 65%).

Elemental analysis (C₃₃ H₃₈ N₆ O₈), % calculated: C 58.39, H 5.64, N 12.38; % found: C 58.49, H 5.61, N 12.03.

1H NMR, d6-DMSO (ppm): 1.34 s, 9H; 2.70 t, 2H; 3.09 m, 6H; 3.57 s, 4H; 4.74 s, 2H; 6.71-7.21 m, 9H; 7.89 d, 2H; 8.34 d, 2H; 10.16 s, 1H; 10.63 s, 1H.

Melting point: 237° C.

26--N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide hydrochloride

The compound 26D (2.76 g, 4.06 mmol), in suspension in toluene (82 ml), is treated at room temperature with trifluoroacetic acid (11 ml). After stirring for 3 h, the mixture is evaporated to dryness and coevaporated 4 times with toluene. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of an orangey-yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 26 (2.38 g, 90%).

The examples 27 to 34 are prepared according to the method described for the preparation of Example 3 from 2A. ##STR47##

    __________________________________________________________________________     Examples                                                                            Y             Reactants    Base/solvents/T °C.                                                               Yd (%)                                                                              M.p. (°C.)                                                                    Empirical                 __________________________________________________________________________                                                          formulae                  27                                                                                                 ##STR48##   Et.sub.3 N/CH.sub.2 Cl.sub.2 /50°                                       C.        16   244   C.sub.24 H.sub.29                                                              N.sub.5 O.sub.4.2HCl                                                           7                         28                                                                                   ##STR49##                                                                                    ##STR50##   Et.sub.3 N/CH.sub.2 Cl.sub.2 /25°                                       C.        31   176   C.sub.30 H.sub.33                                                              N.sub.5 O.sub.3.2HCl                                                           9                         29                                                                                   ##STR51##                                                                                    ##STR52##   pyridine/25° C.                                                                   46   192   C.sub.30 H.sub.33                                                              N.sub.5 O.sub.4.2HCl                                                           .                         30                                                                                   ##STR53##    (CF.sub.3 CO).sub.2 O                                                                       Et.sub.3 N/CH.sub.2 Cl.sub.2 /25°                                       C.        20   183   C.sub.24 H.sub.26                                                              N.sub.5 O.sub.3                                                                F.sub.3.2HCl              31   Me.sub.2 NSO.sub.2                                                                           Me.sub.2 NSO.sub.2 Cl                                                                       pyridine/25° C.                                                                   47   170   C.sub.24 H.sub.32                                                              N.sub.6 O.sub.4                                                                S.sub.1.2HCl              32                                                                                   ##STR54##                                                                                    ##STR55##   pyridine/25° C.                                                                   51   234   C.sub.27 H.sub.29                                                              N.sub.5 O.sub.3                                                                S.sub.1.2HCl              33                                                                                   ##STR56##                                                                                    ##STR57##   Et.sub.3 N/CH.sub.2 Cl.sub.2 /25°                                       C.        28   167   C.sub.29 H.sub.31                                                              N.sub.5 O.sub.4.2HCl      34                                                                                   ##STR58##                                                                                    ##STR59##   pyridine/25° C.                                                                   45   190   C.sub.29 H.sub.30                                                              N.sub.6 O.sub.5.2HCl      __________________________________________________________________________

EXAMPLE 35 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-aminophenyl)piperazin-1-yl!propan-1-one hydrochloride ##STR60## 35A--3- 3-(2-{N-tert -Butoxycarbonyl}aminoethyl)-1H-indol-5-yl!-1- 4-(4-aminophenyl)piperazin-1-yl!propan-1-one

The compound 35A is prepared from the compound 25 (5.8 g, 11.1 mmol) under the conditions described for the preparation of Example 2 from 1C. The pink foam obtained (5.24 g, 96%) is used in the crude state in the following reaction.

35--3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-aminophenyl)piperazin-1-yl!propan-1-one hydrochloride

The product 35A (575 mg, 1.17 mmol) is then deprotected according to the method described for the preparation of Example 2 from 2A.

Purification of the product, in the base form, is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 35 in the form of a pinkish powder (330 mg, 72%).

Elemental analysis (C₂₃ H₃₂ Cl₃ N₅ O.H₂ O), % calculated: C 53.24, H 6.60, N 13.50, Cl 20.50; % found: C 53.40; H 6. illegible!, N 13.53; Cl 18.84.

1H NMR d6-DMSO (ppm): 2.70 t, 2H; 2.88-3.13 m, 10H; 3.63 s, 4H; 4.70 broad s, 3H; 6.97-7.42 m, 8H; 8.15 s, 3H; 10.90 s, 1H.

Melting point: 189° C.

EXAMPLE 36 N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!-propionyl}piperazin-1-yl)phenyl!methanesulfonamide hydrochloride ##STR61##

The compound 36 is prepared from the compound 35A (1.2 g, 2.43 mmol) and mesyl chloride (0.188 ml, 2.43 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 36 in the form of a beige powder (1.06 g, 77%).

Elemental analysis (C₂₄ H₃₃ Cl₂ N₅ O₃ S₁.H₂ O), % calculated: C 51.43, H 6.29, N 12.49, Cl 12.65; % found: C 51.66, H 6.29, N 12.38, Cl 10.59.

1HNMR, d6-DMSO (ppm): 2.70 t, 2H; 2.87-3.15 m, 13H; 3.73 s, 4H; 6.99 d, 1H; 7.18-7.42 m, 7H; 8.13 s, 3H; 9.70 s, 1H; 10.89 s, 1H.

Melting point: 179° C.

Mass spectrum (DCI/NH₃): m/z 470 (M+H)

EXAMPLE 37 N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}piperazin-1-yl)phenyl!-N-dimethylsulfonurea hydrochloride ##STR62##

The compound 37 is prepared from the compound 35A (1.2 g, 2.43 mmol) and dimethylsulfamoyl chloride (0.39 ml, 3.64 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 37 in the form of a beige powder (580 mg, 60%).

Elemental analysis (C₂₅ H₃₆ Cl₂ N₆ O₃ S₁.1.1H₂ O), % calculated: C 50.77, H 6.51, N 14.21, Cl 11.99; % found: C 50.74, H 6.60, N 13.89, Cl 10.61.

1H NMR, d6-DMSO (ppm): 2.66-2.75 m, 8H; 2.88-3.16 m, 10H; 3.76 broad s, 4H; 7.00 d, 1H; 7.15-7.29 m, 6H; 7.43 s, 1H; 8.11 s, 3H; 9.91 s, 1H; 10.89 s, 1H.

Melting point: 166° C.

EXAMPLE 38 N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!-propionyl}piperazin-1-yl)phenyl!-4-nitrobenzenesulfonamide hydrochloride ##STR63##

The compound 38 is prepared from the compound 35A (906 mg, 1.84 mmol) and 4-nitrobenzenesulfonyl chloride (613 mg, 2.76mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of an orange syrup which results, after treatment with hydrochloric acid in ether, in the compound 38 in the form of an orange powder (896 mg, 71%).

Elemental analysis (C₂₉ H₃₄ Cl₂ N₆ O₅ S.2H₂ O), % calculated: C 50.80, H 5.59, N 12.26, Cl 10.34; % found: C 50.83, H 5.50, N 12.11, Cl 10.33.

1H NMR, d6-DMSO (ppm): 2.78 t, 2H; 2.90 t, 2H; 3.00-3.16 m, 8H; 3.66 broad s, 4H; 6.96-7.41 m, 8H; 7.97 d, 2H; 8.09 broad s, 3H; 8.37 d, 2H; 10.56 s, 1H; 10.88 s, 1H.

Melting point: 184° C.

EXAMPLE 39 N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}piperazin-1-yl)phenyl!benzamide hydrochloride ##STR64##

The compound 39 is prepared from the compound 35A (1.08 g, 2.18 mmol) and benzoyl chloride (0.25 ml, 2.18 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 39 in the form of a white powder (869 mg, 68%).

Elemental analysis (C₃₀ H₃₅ Cl₂ N₅ O₂.H₂ O), % calculated: C 61.43; H 6.36; N 11.94, Cl 12.09; % found: C 61.54, H 6.17, N 11.84, Cl 11.79.

1H NMR, d6-DMSO (ppm): 2.72 t, 2H; 2.93-3.01 m, 6H; 3.21 m, 4H; 3.81 broad s, 4H; 7.00 d, 1H; 7.19-7.55 m, 8H; 7.81 d, 2H; 7.97 d, 2H; 8.14 broad s, 3H; 10.39 s, 1H; 10.90 s, 1H.

Melting point: 209° C.

EXAMPLE 40 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-ethyl}piperazin-1-yl)phenylamine hydrochloride ##STR65## 40A: 4-(4-{2- 3-(2-{N-tert-butoxycarbonyl!aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenylamine

The compound 40A is prepared from the compound 23A (7.1 g, 13.9 mmol) according to the conditions described for the preparation of Example 2 from 1C.

The brown syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (1/1, v/v) mixture. The pure product is isolated in the form of a pink foam (6.45 g, 97%).

1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.07 d, 2H; 2.65 m, 4H; 2.75 m, 4H; 2.93 m, 2H; 3.09-3.17 m, 4H; 4.11 t, 2H; 4.56 s, 1H; 6.47-6.58 m, 2H; 6.68-6.75 m, 2H; 6.86-6.90 m, 2H; 7.06-7.08 m, 2H; 7.21 d, 1H; 10.64 s, 1H.

40: 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}-piperazin-1-yl)phenylamine hydrochloride

The product 40A (700 mg, 1.46 mmol), in solution in dichloromethane (12 ml), is treated with a solution (˜1.5M) of hydrochloric acid in ether (16 ml). After stirring for 1 hour, the mixture is evaporated to dryness and the product formed is desalified. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 40 in the form of a pale pink powder (669 mg, 87%).

Elemental analysis (C₂₂ H₃₃ Cl₄ N₅ O.2H₂ O), % calculated: C 48.31, H 6.52, N 12.80, C1 25.93; % found: C 48.31, H 6.65, N 12.55, Cl 24.95.

1H NMR, d6-DMSO (ppm): 3.02 m, 4H; 3.30 m, 4H; 3.65 m, 4H; 3.88 d, 2H; 4.51 broad s, 2H; 6.83 dd, 1H; 7.09-7.33 m, 7H; 8.21 broad s, 3H; 10.35 broad s, 3H; 10.95 s, 1H; 11.59 s, 1H.

Melting point: 200° C. (decomposition).

EXAMPLE 41 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenyl!methanesulfonamide hydrochloride ##STR66##

The compound 41 is prepared from product 40A (1 g, 2.08 mmol) and methanesulfonyl chloride (0.194 ml, 2.50 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 41 in the form of a white powder (1.01 g, 92%).

Elemental analysis (C₂₃ H₃₃ Cl₂ N₅ O₃ s.H₂ O), % calculated: C 50.36, H 6.43, N 12.77, Cl 12.93; % found: C 50.34, H 6.16, N 12.46, Cl 14.31.

1H NMR, d6-DMSO (ppm): 2.86 s, 3H; 3.00 broad s, 4H; 3.15-3.38 m, 4H; 3.60-3.80 m, 6H; 4.48 t, 2H; 6.80 dd, 1H; 6.97 d, 2H; 7.12 d, 2H; 7.20-7.30 m, 3H; 8.17 broad s, 3H; 9.36 s, 1H; 10.91 s, 1H; 11.49 s, 1H

Melting point: 230° C. (decomposition).

EXAMPLE 42 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!methylcarbamate hydrochloride ##STR67##

The compound 42 is prepared from the product 40A (1.5 g, 3.13 mmol) and ethyl chloroformate (0.27 ml; 3.44 mmol) according to the method described for the preparation of Example 6.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a purple syrup which results, after treatment with hydrochloric acid in ether, in the compound 42 in the form of a mauve powder (612 mg, 36%).

Elemental analysis: (C₂₄ H₃₄ Cl₃ N₅ O₃.0.8H₂ O), % calculated: C 51.35, H 6.35, N 12.48, Cl 18.95; % found: C 51.30; H 6.37; N 12.13; Cl 19.02

1HNMR, d6-DMSO (ppm): 3.00-3.30 m, 6H; 3.61 s, 3H; 3.68-3.90 m, 8H; 4.48 t 2H; 6.80 dd, 1H; 6.94 d, 2H; 7.21-7.35 m, 5H; 8.17 broad s, 3H; 9.44 s, 1H; 10.91 s, 1H; 11.41 s, 1H.

Melting point: 166° C. (decomposition).

EXAMPLE 43 2-(5-{2- 4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl)ethoxy}-1-H-indol-3-yl)ethylamine hydrochloride ##STR68##

The compound 43 is prepared from the compound 23A (650 mg, 1.92 mmol) and (2-methoxy-4-nitrophenyl)piperazine (545 mg; 2.3 mmol) according to the conditions described for the preparation of Example 23.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 43 in the form of a yellow powder (777 mg, 79%).

Elemental analysis: (C₂₃ H₃₁ Cl₂ N₅ O₄.1H₂ O), % calculated: C 52.08, H illegible!.27, N 13.20, Cl 13.37; % found: C 52.14; H 6.14; N 13.05; Cl 13.43

1H NMR, d6-DMSO (ppm): 3.03 s, 4H; 3.36 m, 4H; 3.63 m, 4H; 3.83 m, 2H; 3.94 s, 3H; 4.50 t, 2H; 6.84 dd, 1H; 7.13 d, 1H; 7.24-7.32 m, 3H; 7.74 d, 1H; 7.86 dd, 1H; 8.15 broad s, 3H; 10.93 s, 1H; 11.60 s, 1H.

Melting point: 210° C. (decomposition).

EXAMPLE 44 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!piperazin-1-yl)benzonitrile hydrochloride ##STR69## 44A: 4-(4-{2- 3-(2-{N-tert-butoxylcarbonyl}aminoethyl)-1H -indol-5-yloxy!ethyl!piperazin-1-yl)benzonitrile

The compound 44A is prepared from the product 23A (2.8 g, 8.19 mmol) and (4-cyanophenyl)piperazine (3.06 g, 8.19 mmol) according to the method described for the preparation of Example 23.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (5/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup (2.03 g, 50%).

1H NMR, CDCl₃ (ppm): 1.42 s, 9H; 2.74-2.94 m, 8H; 3.36 m, 6H; 4.20 t, 2H; 4.62 broad s, 1H; 6.83 m, 3H; 7.04 dd, 2H; 7.24 m, 1H; 7.50 m, 2H; 8.11 s, 1H.

44: 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!-piperazin-1yl)benzonitrile hydrochloride

The product 44A (707 mg, 1.44 mmol) is then deprotected according to the method described for the preparation of Example 2 from 2A.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 44 in the form of a white powder (496 mg; 76%).

Elemental analysis (C₂₃ H₂₇ N₅ O₁.2.3HCl.H₂ O), % calculated: C 56.22, H 6.42, N 14.25, Cl 16.59; % found: C 56.84, H 6.40, N 14.04, Cl 16.72.

1H NMR, d6-DMSO (ppm): 3.02 s, 4H; 3.37 m, 4H; 3.62 m, 4H; 4.11 m, 2H; 4.49 t, 2H; 6.84 dd, 1H; 7.13 d, 2H; 7.23-7.32 m, 3H; 7.67 d, 2H; 8.14 broad s, 3H; 10.93 s, 1H; 11.58 broad s, 1H.

Melting point: 160° C.

EXAMPLE 45 2-(5-{2- 4-(4-(Aminomethyl)phenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethyl!methylamine hydrochloride ##STR70##

The compound 44A (600 mg, 1.23 mmol), in solution in anhydrous tetrahydrofuran (10 ml), is treated under nitrogen and at 0° C. with a molar solution of lithium aluminum hydride in tetrahydrofuran (2.5 ml, 2.46 mmol). The mixture is then stirred at 80° C. for 12 h. The mixture is then treated with sodium sulfate/water and then filtered through celite.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 45 in the form of a yellow powder (281 mg, 44%).

Elemental analysis: (C₂₄ H₃₆ Cl₃ N₅ O₁.1.3H₂ O), % calculated: C 53.35, H 7.20, N 12.96, Cl 19.68; % found: C 53.37, H 7.19, N 12.70; Cl 19.66.

1H NMR, d6-DMSO (ppm): 3.09-3.28 m, 8H; 3.49-3.93 m, 8H; 4.53 s, 2H; 6.84 dd, 1H; 7.05 d, 2H; 7.23-7.42 m, 5H; 8.39 broad s, 3H; 9.16 broad s, 2H; 10.94 s, 1H; 11.55 broad s, 1H.

Melting point: 84° C. (decomposition).

EXAMPLE 46 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitrile hydrochloride ##STR71## 46A: 2-(4-{2- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitrile

The compound 46A is prepared from (2-cyanophenyl)piperazine (1 g; 5.34 mmol), chloroacetyl chloride (0.43 ml, 5.34 mmol) and the compound 1A (660 mg, 2.39 mmol) according to the procedure described for the preparation of the compound 1B.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (5/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup (1.01 g, 84%).

1H NMR CDCl₃ (ppm): 1.40 s, 9H; 2.88 t, 2H; 3.16 m, 4H; 3.41 t, 2H; 3.84 t, 2H; 4.60 broad s, 1H; 4.75 s, 2H; 6.86 dd, 1H; 6.94-7.09 m, 4H; 7.23 m, 1H; 7.43-7.58 m, H; 8.10 broad s, 1H.

46: 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitrile hydrochloride

The product 46A (741 mg, 1.47 mmol) is then deprotected according to the method described in the preparation of Example 2 from 2A.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 46 in the form of a white powder (388 mg; 60%).

Elemental analysis (C₂₃ H₂₆ ClN₅ O₂.1.4H₂ O), % calculated: C 59.39, H 6.24; N 15.06; Cl 7.62; % found: C 59.72, H 5.85, N 14.79, Cl 8.14.

1HNMR, d6-DMSO (ppm): 3.00-3.20 m, 8H; 3.69 m, 4H; 4.83 s, 2H; 6.79 dd, 1H; 7.10-7.29 m, 5H; 7.58-7.76 m, 2H; 8.08 broad s, 3H; 10.88 s, 1H.

Melting point: 107° C. (decomposition).

EXAMPLE 47 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-aminomethylphenyl)piperazin-1-yl)ethanone hydrochloride ##STR72## 47A: 2- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-(aminomethyl)phenyl)piperazinl-yl)ethanone

The compound 46A (3.4 g; 6.8 mmol), in solution in tetrahydrofuran (114 ml) in the presence of Raney Nickel (˜200 mg, catalytic), is subjected to an atmospheric pressure of hydrogen for 48 hours at room temperature. The mixture is filtered through celite and evaporated to dryness.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (90/9/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup (2.97 g; 86%).

1H NMR, d6-DMSO (ppm): 1.36 s, 9H; 2.70-2.88 m, 6H; 3.17 m, 4H; 3.62 broad s, 4H; 3.77 s, 2H; 4.77 s, 2H; 6.75 dd, 1H; 6.87 t, 1H; 7.00-7.24 m, 6H; 7.43 dd, 1H; 10.65 s, 1H.

47: 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-(aminomethyl)phenyl)piperazinlyl!ethanone hydrochloride

The compound 47A (600 mg; 1.18 mmol) is then deprotected according to the method described for the preparation of Example 40.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 47 in the form of a white powder (506 mg, 83%).

Elemental analysis: (C₂₃ H₃₂ Cl₃ N₅ O₂.1.6H₂ O), % calculated: C 50.62, H 6.50, N 12.83, Cl 19.49; % found: C 50.85, H 6.36, N 12.64, Cl 18.00.

1HNMR, d6-DMSO (ppm): 2.80-2.99 m, 8H; 3.69 broad s, 4H; 4.11 s, 6H; 4.82 s, 2H; 6.77 dd, 1H; 7.15-7.54 m, 7H; 8.16 broad s, 3H; 8.45 broad s, 3H; 10.86 s, 1H.

Melting point: 198° C. (decomposition).

EXAMPLE 48 N- 2- 4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzylmethanesulfonamide hydrochloride ##STR73##

The compound 48 is prepared from the compound 47A (800 mg; 1.58 mmol) and mesyl chloride (0.27 ml; 3.16 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (83/16/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 48 in the form of a white powder (585 mg, 71%).

Elemental analysis: (C₂₄ H₃₁ N₅ O₄ S.1.5HCl.1H₂ O), % calculated: C 51.63, H 6.23, N 12.54, Cl 9.52; % found: C 51.98, H 6.11, N 12.45, Cl 8.94.

1H NMR, d6-DMSO (ppm): 2.80-3.00 m, 11H; 3.67 broad s, 4H; 4.26 d, 2H; 4.82 s, 2H; 6.79 dd, 1H; 7.09-7.47 m, 7H; 8.01 broad s, 3H; 10.85 s, 1H.

Melting point: 250° C.

EXAMPLE 49 N- 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl!benzenesulfonamide hydrochloride ##STR74##

The compound 49 is prepared from the compound 47A (800 mg; 1.58 mmol) and benzenesulfonyl chloride (0.22 ml; 1.70 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19.5/0.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 49 in the form of a white powder (674 mg, 73%).

Elemental analysis: (C₂₉ H₃₄ ClN₅ O₄ S), % calculated: C 59.63, H 5.87, N 11.99, Cl 6.07; % found: C 59.34, H 5.85, N 11.81, Cl 6.21.

1H NMR, d6-DMSO (ppm): 2.75 m, 4H; 3.00 m, 4H; 3.50 broad s, 4H; 4.04 s, 2H; 4.78 s, 2H; 6.77 dd, 1H; 7.01-7.33 m, 7H; 7.55 m, 3H; 7.80 m, 2H; 7.99 broad s, 4H; 10.84 s, 1H.

Melting point: 240° C.

EXAMPLE 50 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)benzonitrile hydrochloride ##STR75## 50A--4-(4-{2- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzonitrile

The compound 50A is prepared from (4-cyanophenyl)piperazine (30.1 g, 160.9 mmol), chloroacetyl chloride (12.8 ml, 160.9 mmol) and the compound 1A (7.2 g, 26.06 mmol) according to the procedure described for the preparation of the compound 1B.

The syrup obtained is chromatographed on a column of silica gel eluted with an ethyl acetate/dichloromethane (2/1, v/v) mixture. The pure product is isolated in the form of a white powder (10.9 g, 83%).

Elemental analysis (C₂₈ H₃₃ N₅ O₄), % calculated: C 66.78, H 6.61, N 13.91, % found: C 66.92, H 6.73, N 13.64.

1H NMR, CDCl3 (ppm): 1.36 s, 9H; 2.83 t, 2H; 3.25-3.40 m, 6H; 3.75 m, 4H; 4.71 s, 2H; 6.83 m, 3H; 6.97 s, 1H; 7.03 d, 1H; 7.22 d, 1H; 7.45 m, 2H; 8.75 broad s, 1H.

50--4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzonitrile hydrochloride

The product 50A (1 g, 1.98 mmol) is then deprotected according to the method described for the preparation of Example 1 from 2A.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 50 in the form of a white powder (728 mg, 88%).

Elemental analysis (C₂₃ H₂₅ N₅ O₂.1.3HCl.0.8H₂ O), % calculated: C 59.37, H 6.04, N 15.05, Cl 9.91; % found: C 59.46, H 5.92, N 14.87, Cl 9.77.

1H NMR, d6-DMSO (ppm): 2.99 m, 4H; 3.45 m, 4H; 3.68 m, 4H; 4.83 s, 2H; 6.78 dd, 1H; 7.03 d, 2H; 7.19 dd, 2H; 7.26 d, 1H; 7.61 d, 2H; 8.03 broad s, 3H; 10.86 s, 1H.

Melting point: 224°-226° C.

EXAMPLE 51 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(aminomethyl)phenyl)piperazin-1-yl!ethanone hydrochloride ##STR76## 51A: 2- 3-(2-{N-tert -Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(aminomethyl)phenyl)piperazin-1-yl!-ethanone

The compound 50A (800 mg, 1.59 mmol) is hydrogenated under the conditions described for the preparation of the product 47A from 46A.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup (800 mg, 99%).

1H NMR, CDCl₃ (ppm): 1.44 s, 9H; 2.91 t, 2H; 3.17 m, 4H; 3.46 m, 2H; 3.80 m, 6H; 4.66 broad s, 1H; 4.78 s, 2H; 6.90 m, 3H; 7.02 d, 1H; 7.11 d, 1H; 7.21-7.29 m, 4H; 8.14 broad s, 1H.

51: 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(aminomethyl)phenyl)piperazin-1-yl!ethanone hydrochloride

The compound 51A (500 mg, 0.98 mmol) is then deprotected under the conditions described for the preparation of Example 2 from 2A.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (75/20/5, v/v) mixture. The pure product is isolated in the form of a beige solid which results, after treatment with hydrochloric acid in ether in the compound 51 in the form of a pale yellow powder (304 mg, 60%).

Elemental analysis (C₂₃ H₃₂ Cl₃ N₅ O₂.1.5H₂ O), % calculated: C 50.79, H 6.49, N 12.88, Cl 19.55; % found: C 50.68, H 6.46, N 12.71, Cl 20.09.

1HNMR, d6-DMSO (ppm): 2.98 broad s, 4H; 3.20-3.37 m, 4H; 3.69 m, 4H; 3.90 m, 2H; 4.82 s, 2H; 6.77 dd, 1H; 7.10 d, 2H; 7.18 d, 2H; 7.25 d, 1H; 7.38 d, 2H; 8.13 broad s, 3H; 8.35 broad s, 3H; 10.85 s, 1H.

Melting point: 185° C. (decomposition).

EXAMPLE 52 N- 4-(4-(2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)benzyl!methanesulfonamide hydrochloride ##STR77##

The compound 52 is prepared from the product 51A (900 mg, 1.77 mmol) and mesyl chloride (0.14 ml, 1.77 mmol) under the conditions described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a beige solid which results, after treatment with hydrochloric acid in ether, in the compound 52 in the form of a white powder (277 mg, 28%).

Elemental analysis (C₂₄ H₃₃ Cl₂ N₅ O₄ S.0.3H₂ O), % calculated: C 51.12, H 6.01, N 12.42, Cl 12.57; % found: C 51.12, H 6.15, N 12.26, Cl 11.78.

1HNMR, d6-DMSO (ppm): 2.80 s, 3H; 2.97 broad s, 4H; 3.25 m, 4H; 3.74 m, 4H; 4.05 s, 2H; 4.81 s, 2H; 6.75 dd, 1H; 7.17-7.29 m, 7H; 7.49 broad s, 1H; 8.05 broad s, 3H; 10.83 s, 1H.

Melting point: 154° C. (decomposition).

EXAMPLE 53 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-amino-2-methoxyphenyl)piperazin-1-yl!ethanone hydrochloride ##STR78## 53A: 2- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-amino-2-methoxyphenyl)piperazin-1-yl!ethanone

The compound 22 in its protected form (NHBOC) (3.06 g, 5.53 mmol) is treated under the conditions described for the preparation of Example 2 from 1C.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (2/1, v/v) mixture. The pure product is isolated in the form of a beige foam (2.3 g, 81%).

1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.72 m, 6H; 3.18 m, 2H; 3.60-3.75 m, 7H; 4.77 s, 2H; 6.05-6.31 m, 2H; 6.75-6.89 m, 2H; 7.07 dd, 2H; 7.23 d, 1H; 10.67 s, 1H.

53: 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-amino-2-methoxyphenyl)piperazin-1-yl!ethanone hydrochloride

The compound 53A (600 mg, 1.14 mmol) is then deprotected according to the method described for the preparation of Example 40 from 40A.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 53 in the form of a white powder (441 mg, 73%).

Elemental analysis (C₂₃ H₃₂ Cl₃ N₅ O₃.2.2H₂ O), % calculated: C 48.25, H 6.41, N 12.23, Cl 18.58; % found: C 48.03, H 6.19, N 12.06, Cl 18.72.

1H NMR, d6-DMSO (ppm): 3.00-3.16 m, 8H; 3.71 m, 4H; 3.81 s, 3H; 4.83 s, 2H; 6.77-6.96 m, 3H; 7.10-7.29 m, 4H; 8.14 broad s, 3H; 10.87 s, 1H.

Melting point: ˜190° C.

EXAMPLE 54 N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)-3-methoxyphenyl!methanesulfonamide hydrochloride ##STR79##

The compound 54 is prepared from the product 53A (1.0 g, 1.91 mmol) and mesyl chloride (0.16 ml, 2.10 mmol) according to the method described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a beige solid which results, after treatment with hydrochloric acid in ether, in the compound 54 in the form of a beige powder (745 mg; 68%).

Elemental analysis (C₂₄ H₃₃ Cl₂ N₅ O₅ S.2H₂ O), % calculated: C 47.21, H 6.11, N 11.47, Cl 11.61; % found: C 47.49; H 5.82; N 11.29, Cl 11.76.

1HNMR, d6-DMSO (ppm): 2.97-3.16 m, 11H; 3.79 m, 7H; 4.82 s, 2H; 6.80 dd, 1H; 6.85 d, 2H; 7.10-7.28 m, 4H; 8.04 broad s, 3H; 9.68 s, 1H; 10.85 s, 1H.

Melting point: 195° C. (decomposition).

EXAMPLE 55 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitronaphth-1-yl)piperazin-1-yl!ethanone hydrochloride ##STR80##

The compound 55 is prepared from (4-nitronaphthyl)piperazine (2.47 g, 9.56 mmol), chloroacetyl chloride (1.37 ml, 17.2 mmol) and the compound 1A (350 mg, 1.26 mmol) according to the method described for the preparation of Example 1.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of yellow crystals which results, after treatment with hydrochloric acid in ether, in the compound 55 in the form of an orange powder (340 mg, 49%).

Elemental analysis (C₂₆ H₂₈ ClN₅ O₄.2H₂ O), % calculated: C 57.19, H 5.91, N 12.83, Cl 6.49; % found: C 57.59, H 5.52, N 12.69, Cl 7.02.

1H NMR, d6-DMSO (ppm): 2.97 m, 4H; 3.13-3.21 m, 4H; 3.82 m, 4H; 4.84 s, 2H; 6.78 dd, 1H; 7.17-7.27 m, 4H; illegible!65-7.82 m, 2H; 8.01 large s, 3H; 8.26-8.35 m, 2H; 8.51 d, 1H; 10.84 s, l illegible!.

Melting point: 183° C.

EXAMPLE 56 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl methanesulfonate hydrochloride ##STR81##

The compound 56 is prepared from 4-(piperazin-1-yl)phenyl methanesulfonate (1.62 g, 6.3 mmol), chloroacetyl chloride (0.60 ml, 7.54 mmol) and the compound 1A (1.16 g, 4.2 mmol) according to the method described for the preparation of Example 1.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 56 in the form of a beige powder (504 mg, 22%).

Elemental analysis (C₂₃ H₃₀ Cl₂ N₄ O₅ S.1H₂ O), % calculated: C 49.18, H 5.71, N 9.97, Cl 12.62; % found: C 49.13, H 5.67, N 9.82, Cl 11.39.

1H NMR, d6-DMSO (ppm): 2.97 m, 4H; 3.22 s, 4H; 3.29 s, 3H; 3.65 m, 4H; 4.80 s, 2H; 6.77 dd, 1H; 7.02-7.26 m, 7H; 8.00 broad s, 3H; 10.84 s, 1H.

Melting point: 238°-240° C. (decomposition).

EXAMPLE 57 6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one hydrochloride ##STR82## 57A: 6-Chloro-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one

(4-Nitrophenyl)piperazine (3.0 g, 14.48 mmol) in solution in methyl ethyl ketone (105 ml) in the presence of potassium carbonate (6 g, 43.4 mmol), is treated under nitrogen and at 0° C. with 6-chlorohexanoic chloride (10.2 g, 15mmol). After stirring for 2 hours from 0° C. to room temperature, the mixture is diluted with ethyl acetate and washed with sodium hydroxide solution (2N) and then with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (30/1 then 10/1, v/v) mixture. The product 57A is obtained in the form of yellow crystals (4.1 g, 84%).

57B: 6- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one

A mixture of the compound 1A (1.87 g, 6.77 mmol) and the compound 57A (4.1 g, 12.2 mmol) in dimethylformamide (11 ml) in the presence of cesium carbonate (3.3 g, 10.1 mmol) is heated at 70° C. for 24 h. The mixture is diluted with ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/ethyl acetate (2/1 then 1/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup (2.5 g, 63%).

1H NMR, d6-DMSO (ppm): 1.34 s, 9H; 1.44-1.72 m, 6H; 2.36 t, 2H; 2.70 t, 2H; 3.12 m, 2H; 3.46 m, 4H; 3.56 m, 4H; 3.92 t, 2H; 6.66 dd, 1H; 6.84 t, 1H; 6.96 m, 3H; 7.04 d, 1H; 7.17 d, 1H; 8.04 d, 2H; 10.58 s, 1H.

57: 6- 3-(2-Aminoethyl)-1H-indol-B-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one hydrochloride

The compound 57B (500 mg; 0.86 mmol) is then deprotected according to the method described for the preparation of Example 1 from 1C.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 57 in the form of a yellow powder (315 mg, 71%).

Elemental analysis (C₂₆ H₃₄ ClN₅ O₄.1H₂ O), % calculated: C 58.08, H 6.77, N 13.02, Cl 7.25; % found: C 57.96, H 6.47, N 12.73, Cl 7.48.

1H NMR, d6-DMSO (ppm): 1.44-1.76 m, 6H; 2.37 t, 2H; 2.96 m, 4H; 3.54 m, 8H; 3.94 t, 2H; 6.70 dd, 1H; 6.95-7.04 m, 3H; 7.15-7.23 m, 2H; 8.02 m, 5H; 10.77 s, 1H.

Melting point: 100° C.

EXAMPLE 58 6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-aminophenyl)piperazin-1-yl!hexan-1-one hydrochloride ##STR83## 58A: 6-(3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol -5-yloxy!-1- 4-(4-aminophenyl)piperazin-1-yl!hexan-1-one

The compound 57B (2.01 g, 3.46 mmol) is hydrogenated under the conditions described for the preparation of Example 2A.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (3/1, v/v) mixture. The pure product is isolated in the form of a beige syrup (1.89 g, 99%).

1H NMR, d6-DMSO (ppm): 1.35 s, 9H; 1.40-1.72 m, 6H; 2.34 t, 2H; 2.68-2.86 m, 6H; 3.12 m, 2H; 3.52 broad s, 4H; 3.92 t, 2H; 4.59 s, 2H; 6.46 d, 2H; 6.67 m, 3H; 6.84 t, 1H; 7.00 dd, 2H; 7.17 d, 1H.

58: 6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-aminophenyl)piperazin-1-yl!hexan-1-one hydrochloride

The compound 58A (500 mg, 0.91 mmol) is then deprotected under the conditions described for the preparation of Example 1 from 1C.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 58 in the form of a pale pink powder (270 mg, 60%).

Elemental analysis (C₂₆ H₃₈ Cl₃ N₅ O₂.1.4H₂ O), % calculated: C 53.46, H 7.04; N 11.99, Cl 18.21; % found: C 53.44, H 6.96, N 11.80, Cl 17.13.

1H NMR, d6-DMSO (ppm): 1.40-1.80 m, 6H; 2.40 t, 2H; 2.99 broad s, 4H; 3.18 broad s, 4H; 3.64 m, 4H; 3.97 t, 2H; 6.70 dd, 1H; 7.07-7.28 m, 7H; 8.09 broad s, 3H; 10.82 s, 1H.

Melting point: 150° C.

EXAMPLE 59 N- 4-(4-{6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanoyl}piperazin-1-yl)phenyl!methane sulfonamide hydrochloride ##STR84##

The compound 59 is prepared from the product 58A (690 mg, 1.25 mmol) and mesyl chloride (107 μl, 1.37 mmol) under the conditions described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a pale yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 59 in the form of a beige powder (658 mg, 92%).

Elemental analysis (C₂₇ H₃₉ Cl₂ N₅ O₄ S.0.5H₂ O.0.3EtOH), % calculated: C 53.20, H 6.61, N 11.49, Cl 11.63; % found: C 53.24, H 6.96, N 11.10, Cl 10.12.

1H NMR, d6-DMSO (ppm): 1.53-1.75 m, 6H; 2.41 t, 2H; 2.93 s, 3H; 2.99 broad s, 4H; 3.23 broad s, 4H; 3.72 broad s, 4H; 3.97 t, 2H; 6.75 d, 1H; 7.07-7.25 m, 7H; 8.04 broad s, 3H; 9.62 s, 1H; 10.81 s, 1H.

Melting point: 141° C.

EXAMPLE 60 N- 4-(4-{6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanol}piperazin-1-yl)benzyl!benzenesulfonamide hydrochloride ##STR85##

The compound 60 is prepared from the product 58A (690 mg, 1.25 mmol) and benzenesulfonyl chloride (176 μl, 1.37 mmol) under the conditions described for the preparation of Example 3.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a beige syrup which results, after treatment with hydrochloric acid in ether, in the compound 60 in the form of a beige powder (550 mg, 67%).

Elemental analysis (C₃₂ H₄₁ Cl₂ N₅ O₄ S.0.5H₂ O % calculated: C 57.22, H 6.30, N 10.43, Cl 10.56; % found: C 57.31, H 6.20, N 10.18, Cl 9.41.

1HNMR, d6-DMSO (ppm): 1.52-1.75 m, 6H; 2.34 t, 2H; 2.99-3.08 m, 8H; 3.61 broad s, 4H; 3.96 t, 2H; 6.73 dd, 1H; 6.97-7.26 m, 7H; 7.53-7.74 m, 5H; 8.05 broad s, 3H; 10.05 s, 1H; 10.82 s, 1H.

Melting point: 132° C.

EXAMPLE 61 5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!pentan-1-one hydrochloride ##STR86## 61A: 5- 3-(2-{N-tert-Butoxycarbonyl}aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!pentan-1-one

The compound 61A is prepared from (4-nitrophenyl)piperazine (1.1 g, 5.20 mmol), 5-chloropentanoyl chloride (2.6 ml, 20.8 mmol) and the compound 1A (800 mg, 2.89 mmol) under the conditions described for the preparation of the compound 57B.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (10/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup (685 mg, 42%).

1H NMR, d6-DMSO (ppm): 1.35 s, 9H; 1.71 m, 4H; 2.46 t, 2H; 2.70 t, 2H; 3.13 m, 2H; 3.47 m, 4H; 3.58 broad s, 4H; 3.95 t, 2H; 6.69 dd, 1H; 6.84 t, 1H; 6.95-7.19 m, 5H; 8.05 d, 2H; 10.58 s, 1H.

61: 5- 3-(2-Aminoethyl)-1H-indol-5-yloxyl-1- 4-(4-nitrophenyl)piperazin-1-yl!pentan-1-one hydrochloride

The product 61A (300 mg, 0.530 mmol) is then deprotected under the conditions described for the preparation of Example 1 from 1C.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v)mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 61 in the form of a yellow powder (211 mg, 75%).

Elemental analysis (C₂₅ H₃₂ ClN₅ O₄.1.7H₂ O), % calculated: C 56.38, H 6.70, N 13.15, Cl 6.66; % found: C 56.33, H 6.58, N 12.88, Cl 7.34.

1H NMR, d6-DMSO (ppm): 1.75 m, 4H; 2.46 t, 2H; 2.99 m, 4H; 3.51 m, 4H; 3.62 broad s, 4H; 4.00 t, 2H; 6.73 dd, 1H; 6.99-7.27 m, 5H; 7.99 broad s, 3H; 8.08 d, 2H; 10.80 s, 1H.

Melting point: 120° C.

EXAMPLE 62 5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(aminophenyl)piperazin-1-yl!pentan-1-one hydrochloride ##STR87##

The compound 62 is prepared from the product 61A (560 mg, 0.99 mmol) under the conditions described for the preparation of Example 2.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18.5/1.5, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 62 in the form of a pink powder (270 mg, 50%).

Elemental analysis (C₂₅ H₃₆ Cl₃ N₅ O₂.1.5H₂ O), % calculated: C 52.50, H 6.87, N 12.24, Cl 18.59; % found: C 52.42, H 6.94, N 12.01, Cl 17.36.

1H NMR d6-DMSO (ppm): 1.72 broad s, 4H; 2.43 t, 2H; 2.97 broad s, 4H; 3.14 m, 4H; 3.62 broad s, 4H; 3.97 t, 2H; 6.71 dd, 1H; 7.06-7.24 m, 7H; 8.03 broad s, 3H; 10.79 s, 1H.

Melting point: 170° C.

EXAMPLE 63 4- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!butan-1-one hydrochloride ##STR88##

The compound 63 is prepared from (4-nitrophenyl)piperazine (2.0 g, 9.65 mmol), 4-chlorobutanoyl chloride (4.3 ml, 38.6 mmol) and the compound 1A (1.48 g, 5.36 mmol) under the conditions described for the preparation of Example 57.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/19/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup which results, after treatment with hydrochloric acid in ether, in the compound 63 in the form of a yellow powder (919 mg, 35%).

Elemental analysis (C₂₄ H₃₀ ClN₅ O₄.H₂ O), % calculated: C 56.97, H 6.37, N 13.84, Cl 7.01; % found: C 56.88, H 6.12, N 13.68, Cl 8.89.

1HNMR, d6-DMSO (ppm): 1.96 t, 2H; 2.54 t, 2H; 2.97 broad s, 4H; 3.49 m, 4H; 3.61 m, 4H; 4.00 t, 2H; 6.72 dd, 1H; 6.95-7.25 m, 5H; 8.05 m, 5H; 10.82 s, 1H.

Melting point: 120° C.

EXAMPLE 64 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-cyanophenylsulfonamide hydrochloride ##STR89## 64A: N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-cyanobenzenesulfonamide

The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 0° C. with 4-cyanobenzenesulfonyl chloride (2.18 g, 10.81 mmol). After stirring for 4 h from 0° C. to room temperature, 4-cyanobenzenesulfonyl chloride (0.64 g, 3.24 mmol) is again added. After 2 h 00, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The dark green syrup obtained is chromatographed on a column of silica gel, eluted with a dichloromethane/acetone (25/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup (3.28 g, 69%).

Elemental analysis (C₂₂ H₂₆ N₄ O₄ S₁.0.6H₂ O), % calculated: C 58.29, H 6.07, N 12.36, % found: C 58.17, H 5.76, N 12.03.

1H NMR, d6-DMSO (ppm): 1.37 s, 9H; 2.97 t, 4H; 3.35 m, 4H; 6.83 q, 4H; 7.79 d, 2H; 8.00 d, 2H; 10.08 s, 1H.

64: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-cyanophenylsulfonamide hydrochloride

The compound 64 is prepared from the product 64A (3.2 g, 7.23 mmol) under the conditions described for the preparation of Example 26 from 26B.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 64 (1.1 g).

EXAMPLE 65 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-(trifluoromethane)phenylsulfonamide hydrochloride ##STR90## 65A: N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-(trifluoromethane)benzenesulfonamide

The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 0° C. with 4-(trifluoromethane)benzenesulfonyl chloride (2.64 g, 10.81 mmol). After stirring for 4 h from 0° C. to room temperature, 4-cyanobenzenesulfonyl chloride (0.75 g, 3.24 mmol) is again added. After 2 h 00, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (30/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup (3.50 g, 67%).

Elemental analysis (C₂₂ H₂₆ N₃ O₄ S₁ F₃.0.4H₂ O), % calculated: C 53.63, H 5.48, N 8.53; % found: C 53.61, H 5.61, N 8.40.

1H NMR, d6-DMSO (ppm): 1.41 s, 9H; 3.00 t, 4H; 3.38 m, 4H; 6.87 q, 4H; 7.91 q, 4H; 10.13 broad s, 1H.

65: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-(trifluoromethane)phenylsulfonamide hydrochloride

The compound 65 is prepared from the product 65A (3.5 g, 7.20 mmol) under the conditions described for the preparation of Example 26 from 26B.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 65 (0.97 g).

EXAMPLE 66 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-methoxyphenylsulfonamide hydrochloride ##STR91## 66A: N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-methoxybenzenesulfonamide

The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 0° C. with 4-methoxybenzenesulfonyl chloride (2.23 g, 10.81 mmol). After stirring for 4 h from 0° C. to room temperature, 4-methoxybenzenesulfonyl chloride (0.67 g, 3.24 mmol) is again added. After 2 h 00, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (30/1, v/v) mixture. The pure product is isolated in the form of a yellow syrup (4.1 g, 84%).

Elemental analysis (C₂₂ H₂₉ N₃ O₅ S₁.0.3H₂ O), % calculated: C 58.34, H 6.59, N 9.28; % found: C 58.38, H 6.49, N 9.08.

1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.96 t, 4H; 3.38 t, 4H; 3.77 s, 3H; 6.83 q, 4H; 7.01 d, 2H; 7.58 d, 2H; 9.69 s, 1H.

66: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-methoxyphenylsulfonamide hydrochloride

The compound 66 is prepared from the product 66A (4.1 g, 9.1 mmol) under the conditions described for the preparation of Example 26 from 26B.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 66 (1.6 g).

EXAMPLE 67 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-fluorophenylsulfonamide hydrochloride ##STR92## 67A: N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-fluorobenzenesulfonamide

The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 0° C. with 4-fluorobenzenesulfonyl chloride (2.1 g, 10.81 mmol). After stirring for 4 h from 0° C. to room temperature, 4-fluorobenzenesulfonyl chloride (0.63 g, 3.24 mmol) is again added. After 2 h 00, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel, eluted with a dichloromethane/acetone (30/1, v/v) mixture. The pure product is isolated in the form of a yellow foam (3.6 g, 76%).

Elemental analysis (C₂₁ H₂₆ N₃ O₄ S₁ F₁.0.3H₂ O), % calculated: C 57.21, H 6.08, N 9.53; % found: C 57.36, H 6.01, N 9.45.

1H NMR, d6-DMSO (ppm): 1.39 s, 9H; 2.98 t, 4H; 3.39 t, 4H; 6.84 q, 4H; 7.36 m, 2H; 7.71 m, 2H; 9.86 s, 1H.

67: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-fluorophenylsulfonamide hydrochloride

The compound 67 is prepared from the product 67A (3.6 g, 8.26 mmol) under the conditions described for the preparation of Example 26 from 26B.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (85/14/1, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 67 (1.2 g).

EXAMPLE 68 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-acetamidophenylsulfonamide hydrochloride ##STR93## 68A: N- 4-(4-(tert-Butoxycarbonyl)piperazin-1-ylphenyl)-4-acetamidobenzenesulfonamide

The compound 26A (3.0 g, 10.81 mmol), in solution in dichloromethane (80 ml) in the presence of triethylamine (2.21 ml, 11.89 mmol), is treated at 0° C. with 4-acetamidobenzenesulfonyl chloride (2.5 g, 10.81 mmol). After stirring for 4 h from 0° to room temperature, 4-acetamidobenzenesulfonyl chloride (0.76 g, 3.24 mmol) is again added. After 1 h 00, the reaction mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/acetone (6/1, v/v) mixture. The pure product is isolated in the form of a purple foam (3.5 g, 69%).

Elemental analysis (C₂₃ H₃₀ N₄ O₅ S₁.1H₂ O), % calculated: C 56.08, H 6.55, N 11.37; % found: C 56.16, H 6.29, N 11.00.

1H NMR, d6-DMSO (ppm): 1.38 s, 9H; 2.03 s, 3H; 2.95 t, 4H; 3.37 t, 4H; 6.82 q, 4H; 7.60 q, 4H; 9.70 s, 1H; 10.26 s, 1H.

68: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-acetamidophenylsulfonamide hydrochloride

The compound 68 is prepared from the product 68A (3.6 g, 8.26 mmol) under the conditions described for the preparation of Example 26 from 26B.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 68 (1.1 g).

EXAMPLE 69 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-aminophenylsulfonamide hydrochloride ##STR94## 69A: N- 4-(4-{2- 3-(2-{N-tert-Butoxycarbonyl}amino)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-aminophenylsulfonamide hydrochloride

The compound 69A is prepared from the compound 26C (1.3 g, 1.96 mmol) according to the method described for the preparation of Example 2A from 1C.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (95/4/1, v/v) mixture. The pure product is isolated in the form of an orange foam (1.2 g, 95%).

1H NMR, d6-DMSO (ppm): 1.37 s, 9H; 2.73 t, 2H; 3.03-3.16 m, 6H; 3.60 broad s, 4H; 4.77 s, 2H; 5.91 s, 2H; 6.50 d, 2H; 6.74-6.93 m, 6H; 7.06 dd, 2H; 7.20-7.33 m, 4H, 9.41 s, 1H; 10.66 s, 1H.

69: N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-aminophenylsulfonamide hydrochloride

The compound 69A (560 mg, 0.86 mmol) is then deprotected under the conditions described for the preparation of Example 1 from 1C.

Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a colorless syrup which results, after treatment with hydrochloric acid in ether, in the compound 69 in the form of a white powder (407 mg, 72%).

Elemental analysis (C₂₈ H₃₅ Cl₃ N₆ O₄.3.2H₂ O), % calculated: C 46.99, H 5.83, N 11.74, Cl 14.86; % found: C 46.95, H 5.82, N 11.42, Cl 14.37.

1HNMR, d6-DMSO (ppm) 2.96 broad s, 4H; 3.23 broad d, 4H; 3.71 m, 4H; 4.79 s, 2H; 6.56 d, 2H; 6.75 dd, 1H; 6.92-7.38 m, 9H; 8.01 broad s, 3H; 9.75 s, 1H; 10.82 s, 1H.

Melting point: 186° C.

EXAMPLE 70 N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)phenyl!-4-(methanesulfonylamino)phenylsulfonamide hydrochloride ##STR95##

The compound 70 is prepared from the compound 69A (300 mg, 0.46 mmol) and methanesulfonyl chloride (36 μl, 1.46 mmol) according to the method described for the preparation of Example 3.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane/methanol/aqueous ammonia (80/18/2, v/v) mixture. The pure product is isolated in the form of a syrup which results, after treatment with hydrochloric acid in ether, in the compound 70 (30 mg, 10%).

The specific compounds of the present invention, then, may be identified as follows:

A compound selected from the group consisting of:

2- 3-(2-Aminoethyl)-1-H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(aminophenyl)piperazin-1-yl!ethanone.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!acetamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!benzamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methethanesulfonamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1-methylsulfonyl-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!methanesulfonamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!ethanesulfonamide.

Thiophene-2-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide.

Thiophene-2-{N- 4-(4-{2- 3-(2-aminoethyl)-1-(thiophene-2-sulfonyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide.

3,5-Dimethylisoxazole-4-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-N-{ethoxycarbonyl}aminophenyl)piperazin-1-yl!ethanone.

2,2,2-Trifluoroethane 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!isopropanesulfonamide.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-nitrophenyl)piperazin-1-yl)ethanone.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl)ethanethione.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(hydroxyamino)phenyl)piperazin-1-yl)ethanone.

2-{5- 4-(4-Nitrophenylpiperazine -1-sulfonylmethoxy!-1H-indol-3-yl}ethylamine.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!propane-1-one.

2- 3-(2-(Dimethylamino)ethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(dimethylamino)phenyl)piperazin-1-yl!ethanone.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!benzenesulfonamide.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-methoxy-4-nitrophenyl)piperazin-1-yl!ethanone.

2-(5-{2- 4-(4-Nitrophenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethylamine.

3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!prop-2-en-1-one.

3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!propan-1-one.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2-phenylacetamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2-methoxybenzamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2,2,2-trifluoroacetamide.

3- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-1,1-dimethylsulfonurea.

Thiophene-2-carboxylic acid 4-(4-{2- 3-2-aminoethyl) indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!amide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!phenylcarbamate.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-nitrobenzamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methylcarbamate.

3- 3-(2-Aminoethyl)-1H -indol-5-yl!-1- 4-(4-aminophenyl)-piperazin-1-yl!propan-1-one.

N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!methanesulfonamide.

N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!-N-dimethylsulfonylurea.

N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!-4-nitrobenzenesulfonamide.

N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!benzamide.

4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-ethyl}piperazin-1-yl)phenylamine.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenyl!methanesulfonamide.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methylcarbamate.

2-(5-{2- 4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl) -ethoxy}-1-H-indol-3-yl)ethylamine.

4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!-piperazin-1-yl)benzonitrile.

2-(5-{2- 4-(4-(Aminomethyl)phenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethyl!methylamine.

2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)benzonitrile.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-aminomethylphenyl)piperazin-1-yl!ethanone.

N- 2- 4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzylmethanesulfonamide.

N- 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl!benzenesulfonamide.

4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzonitrile.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(aminomethyl)phenyl)piperazin-1-yl!ethanone.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzyl!methane sulfonamide.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-amino-2-methoxyphenyl)piperazin-1-yl!ethanone.

N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)-3-methoxyphenyl!methanesulfonamide.

2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitronaphth-1-yl)piperazin-1-yl!ethanone.

4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl methanesulfonate.

6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one.

6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-aminophenyl)piperazin-1-yl!hexan-1-one.

N- 4-(4-{6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanoyl}-piperazin-1-yl)phenyl!methanesulfonamide.

N- 4-(4-{6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanol}-piperazin-1-yl)benzyl!benzenesulfonamide.

5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!pentan-1-one.

5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(aminophenyl)-piperazin-1-yl!-pentan-1-one.

4- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!butan-1-one.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-cyanophenylsulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-(trifluoromethane)phenyl sulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-methoxyphenylsulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-fluorophenylsulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-acetamidophenylsulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-aminophenylsulfonamide.

N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-(methanesulfonylamino)phenylsulfonamide, and

their salts which are acceptable for therapeutic use.

STUDY OF THE AFFINITY FOR 5-HT_(1D) RECEPTORS

This study is carried out according to the technique described by Pauwells et al. (Biochem. Pharmacol, 46, 535-538, 1993).

Preparation of the membranes

Sheep brains are removed in the local abattoir and transported in ice. The caudate nuclei are removed, weighed and homogenized with a Polytron for 20 sec (speed 6-7) in 20 volumes of Tris-HCl 50 mM, pH 7.7. The homogenate is centrifuged for 10 min at 48,000 g with an L5 50E centrifuge (Beckman).

The pellet, taken up in 20 volumes of Tris-HCl 50 mm, pH 7.7, is placed in a water bath at 37° C. for 10 min and then recentrifuged for 10 min at 48,000 g. The pellet then obtained is immediately frozen in fractions containing 0.5g of tissue.

Affinities

The pellet is defrosted and homogenized with a Dounce in 80 volumes of Tris-HCl 50 mM, pH 7.7, containing 4 mM CaCl₂, 10 μM of pargyline and 0.1% of ascorbic acid.

Affinity is produced at 25° C. by incubating for 30 min:

0.1 ml of buffer or 10 μM, as final concentration, of sumatriptan, in order to obtain the non-specific binding

0.8 ml of membrane

0.1 ml of 3H-5HT (15 to 30 Ci:mM, New England Nuclear France).

The incubation is brought to an end by rapid filtration through GF/B filters and rinsing with 3 times 3 illegible! ice-cold buffer, using a harvester manufactured by Brandel which makes it possible illegible! to filter illegible!samples. The filters are introduced into vials containing illegible!ml of illegible! illegible! scintillant (Packard) and the radioactivity measured with a Tri-carb 4640 counter (Packard). The IC₅₀ (concentration which inhibits the specific affinity by 50%) is determined graphically.

The affinities of the various products which form part of this invention for 5HT_(1A) and 5HT_(1B) receptors were measured according to the techniques described in:

Peroutka S. J. Pharmacological differentiation and characterization of 5HT_(1A), 5HT_(1B) and 5HT_(1C) binding sites in rat frontal cortex. J. Neurochem., 45, 529-540, 1986.

    ______________________________________                                         Examples of the affinity profile of several molecules                          (IC.sub.50 × 10-9M)                                                                5-HT.sub.1D  5-HT.sub.1A                                                                            Ratio.sup.#                                     Example*  mean         mean    1A/1D                                           ______________________________________                                         4         1            75      75                                              6         4.3          79      18                                              7         1.6          44      28                                              8         1.2          26      22                                              9         5            38       8                                              10        1            20      20                                              11        2.4          105     44                                              14        1            9.5     10                                              ______________________________________                                          *The examples are the ones described in the text in order to illustrate        the invention                                                                  .sup.# Ratio of the IC.sub.50 values of each product for the 5HT.sub.1A        and 5HT.sub.1D receptors                                                 

STUDY OF THE AGONIST ACTIVITY WITH RESPECT TO THE 5-HT_(1B) RECEPTORS

The measurements were carried out with respect to the inhibition of the formation of cAMP stimulated by forskolin, mediated by a 5-HT_(1B) receptor, in an OK kidney epithelial cell line as described elsewhere (P. J. Pauwels and C. Palmier, Neuropharmacology, awaiting publication).

The studies carried out show that the majority of the products of the invention, like serotonin, are capable of effectively blocking the formation of cAMP in this test. Thus, Examples 1, 2, 3 and 5 have an EC₅₀ of between 0.3 and 1.2 nM.

Study of the affinity and of the agonist activity with respect to human receptors

Human 5HT_(1Da) and 5HT_(1Db) receptors were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci., 89, 3630 (1992).

The transient transfection and the stable transfection of the genes of these receptors was carried out in Cos-7 and CHO-K₁ cell lines by using an electroporator.

The HeLa HA7 cell line expressing the 5HT_(1A) human receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultured according to the method of Fargin et al., J. Biol. Chem., 264, 14848 (1989).

The binding of the derivatives of the present invention with human 5HT_(1Da), 5HT_(1Db) and 5HT_(1A) receptors was studied according to the method described by P. Pauwels and C. Palmier (Neuropharmacology, 33, 67, 1994).

The incubation media for these binding measurements comprise 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand 3H!-SCT (final concentration: 2 nM) for the 5HT_(1Da) and 5HT_(1Db) receptors and 3H!-80H-DPAT (final concentration: 1 nM) for the 5HT_(1A) receptor! and 0.05 ml of the molecule to be tested (final concentrations from 0.1 nM to 1000 nM) or 10 μM (final concentration) of serotonin (5HT_(1Da) and 5HT_(1Db)) or 1 μM (final concentration) of spiroxatrin (5HT_(1A) ).

The inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HT_(1Db) receptor was studied in CHO-K1 cells transfected by the receptor according to the technique described previously for the 5HT_(1B) receptor (P. Pauwels and C. Palmier, Neuropharmacology, 33, 67, 1994).

Illustration of the profile of several molecules of the present invention

    ______________________________________                                                 Ki (nM)                                                                Example   5HT.sub.1Da                                                                            5HT.sub.1Db                                                                              5HT.sub.1A                                                                           EC.sub.50 * (nM)                             ______________________________________                                          1        0.5     1         25    1.2                                           3        1.7     3.3       78.6  20                                            5        0.7     3.2       73    6.5                                          26        0.25    0.5       16.5  6.5                                          33        2.8     2         39    9                                            41        1.1     0.7       28    2.6                                          59        1.3     1.3       9.3   0.52                                         ______________________________________                                          *Inhibition of the 5HT.sub.1Db cyclase stimulated by forskolin           

The several examples described above clearly show that the products of the present invention are excellent ligands for human 5HT_(1Da) and 5HT_(1Db) receptors and are excellent agonists with respect to the human 5HT_(1Db) receptor.

The new arylpiperazine-derived indole compounds which form part of this invention are ligands having an exceptional affinity for the 5-HT_(1D) and 5-HT_(1B) receptors, as is demonstrated by the examples described above. Many compounds which are an integral part of the present invention have the additional advantage of being particularly selective for the 5 HT_(1D) receptor with respect to the 5 HT_(1A), 5 HT_(1C), 5 HT₂, α₁, α₂ and D₂ receptors. The selectivity of the compounds of the present invention and in particular their preferential affinity for the 5 HT_(1D) receptor with respect to the 5 HT_(1A) receptor represents a very important advantage with respect to the ligands of the 5 HT_(1D) receptor known to date (cf. Annual Reports in Medicinal Chemistry, vol. 27, chapter 3, p. 25; Academic Press, 1992).

In human therapeutics, the compounds of general formula (I) according to the invention are particularly useful in the treatment and prevention of disorders related to serotonin in the central nervous system and in the vascular system. These compounds can therefore be used in the treatment and prevention of depression, compulsive obsessional disorders, eating disorders, such as bulimia and anorexia, aggressiveness, alcoholism, nicotine addiction, hypertension, nausea, sexual dysfunctioning, asocial behavior, anxiety, migraine, Alzheimer's disease and memory disorders.

The present invention also relates to the medicaments comprising at least one compound of formula (I) in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which can be inert or physiologically active. The medicaments according to the invention can be employed orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules or cachets) or granules can be used as solid compositions for oral administration. In these compositions, the active principle according to the invention is mixed with one or a number of inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions can also comprise substances other than the diluents, for example one or a number of lubricating agents such as magnesium stearate or talc, a coloring agent, a coating agent (dragees) or a varnish.

Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used as liquid compositions for oral administration. These compositions can comprise substances other than the diluents, for example wetting, sweetening, thickening, flavoring or stabilizing substances.

The sterile compositions for parenteral administration can preferably be suspensions, emulsions or nonaqueous or aqueous solutions. Water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents can be used as solvent or vehicle. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They can also be prepared in the form of solid sterile compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, besides the active product, excipients such as cocoa butter, semi-synthetic glycerides or poly(ethylene glycol)s.

The compositions for topical administration can be, for example, creams, lotions, eyedrops, mouthwashes, nosedrops or aerosols.

The doses depend on the desired effect, on the duration of treatment and on the administration route used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally, for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance and preferably from 1 mg to 50 mg.

Generally, the doctor will determine the appropriate dosage depending on the age, weight and all the other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention in these examples, the term "active component" denotes one or a number (generally one) of the compounds of formula (I) according to the present invention!:

Tablets

They can be prepared by direct compression or by passing through a wet granulation. The procedure by direct compression is preferred but it may not be suitable in all cases, depending on the doses and the physical properties of the active component.

A--By direct compression

    ______________________________________                                                           mg for 1 tablet                                              ______________________________________                                         Active component    10.0                                                       Microcrystalline cellulose, B.P.C.                                                                 89.5                                                       Magnesium stearate   0.5                                                                           100.0                                                      ______________________________________                                    

The active component is passed through a sieve with a mesh size of 250 μm per side, mixing is carried out with the excipients and compression is carried out using 6.0 mm dies. Tablets having other mechanical strengths can be prepared by modifying the compressive weight with use of appropriate dies.

B--Wet granulation

    ______________________________________                                                         mg for one tablet                                              ______________________________________                                         Active component  10.0                                                         Lactose, pharmaceutical grade                                                                    74.5                                                         Starch, pharmaceutical grade                                                                     10.0                                                         Pregelatinized maize starch,                                                                      5.0                                                         pharmaceutical grade                                                           Magnesium stearate                                                                                0.5                                                         Weight at compression                                                                            100.0                                                        ______________________________________                                    

The active component is passed through a sieve with a mesh size of 250 μm and mixing is carried out with the lactose, the starch and the pregelatinized starch. The mixed powders are moistened-with purified water, granulation is carried out, drying is carried out, sieving is carried out and mixing with magnesium stearate is carried out. The lubricated granules are compressed as in the direct compression formulae. A thin coating layer can also be applied to the tablets by means of appropriate film-forming materials, for example methylcellulose or hydroxypropylmethylcellulose, according to conventional techniques. The tablets can also be coated with sugar.

Capsules

    ______________________________________                                                       mg for one capsule                                               ______________________________________                                         Active component                                                                               10.0                                                           *Starch 1500    89.5                                                           Magnesium stearate,                                                                             0.5                                                           pharmaceutical grade                                                           Filling weight  100.0                                                          ______________________________________                                          *a form of directly compressible starch supplied by the firm Colorcon Ltd      Orpington, Kent, United Kingdom.                                         

The active component is passed through a sieve with a mesh size of 250 μm and mixing with the other substances is carried out. The mixture is introduced into hard gelatin No. 2 capsules on a suitable filling machine. Other dosage units can be prepared by modifying the filling weight and, when necessary, by changing the size of the capsule.

Syrup

    ______________________________________                                                           mg per dose of 5 ml                                          ______________________________________                                         Active component        10.0                                                   Sucrose, pharmaceutical grade                                                                          2750.0                                                 Glycerol, pharmaceutical grade                                                                         500.0                                                  Buffer                                                                         Flavor                                                                         Colorant                q.s.                                                   Preservative                                                                   Distilled water         5.0                                                    ______________________________________                                    

The active component, the buffer, the flavor, the colorant and the preservative are dissolved in part of the water and the glycerol is added. The remainder of the water is heated to 80° C. and the sucrose is dissolved therein and the solution is then cooled. The two solutions are combined, the volume is adjusted and mixing is carried out. The syrup obtained is clarified by filtration.

Suppositories

    ______________________________________                                         Active component          10.0      mg                                         *Witepsol H15   remainder to                                                                             1.0       g                                          ______________________________________                                          *Tradename for Adeps Solidus from the European Pharmacopeia.             

A suspension of the active component in Witepsol H15 is prepared and it is introduced into an appropriate machine with 1 g suppository molds.

Liquid for administration by intravenous injection

    ______________________________________                                                              g/l                                                       ______________________________________                                         Active component         2.0                                                   Water for Injection, pharmaceutical grade                                                             1000.0                                                  remainder to                                                                   ______________________________________                                    

It is possible to add sodium chloride in order to adjust the tonicity of the solution and to adjust the pH to the maximum stability and/or in order to facilitate dissolution of the active component by means of a dilute alkali or acid or by adding appropriate buffer salts. The solution is prepared, is clarified and is introduced into phials of appropriate size which are sealed by melting the glass. It is also possible to sterilize the liquid for injection by heating in an autoclave according to one of the acceptable cycles. It is also possible to sterilize the solution by filtration and to introduce into a sterile phial under aseptic conditions. The solution can be introduced into the phials under a gaseous atmosphere.

Cartridges for inhalation

    ______________________________________                                                          g/cartridge                                                   ______________________________________                                         Mironized active component                                                                         1.0                                                        Lactose, pharmaceutical grade                                                                     39.0                                                        ______________________________________                                    

The active component is micronized in a fluid-energy mill and converted to the form of fine particles before mixing with lactose for tablets in a high energy mixer. The pulverulent mixture is introduced into hard gelatin No. 3 capsules on an appropriate encapsulating machine. The contents of the cartridges are administered using a powder inhaler.

Pressurized aerosol with a metering valve

    ______________________________________                                                         mg/dose                                                                              per 1 container                                          ______________________________________                                         Micronized active component                                                                      0.500   120       mg                                         Oleic acid, pharma-                                                                              0.050   12        mg                                         ceutical grade                                                                 Trichloroofluoromethane for                                                                      22.25   5.34      g                                          pharmaceutical use                                                             Dichlorodifluoromethane for                                                                      60.90   14.62     g                                          pharmaceutical use                                                             ______________________________________                                    

The active component is micronized in a fluid-energy mill and reduced to the form of fine particles. The oleic acid is mixed with the trochlorofluoromethane at a temperature of 10°-15° C. and the micronized medicament is introduced into the solution using a mixer with a high shearing effect. The suspension is introduced in a measured amount into aluminum aerosol containers to which are attached appropriate metering valves delivering a dose of 85 mg of the suspension; the dichlorodifluoromethane is introduced into the containers by injection through the valves. 

We claim:
 1. A compound selected from those corresponding to the formula ##STR96## in which: R₁ represents an NH₂, NO₂, NH--NH₂, NH--OH, NCOR₇ (OH), NR₅ R₆, NHCOR₇, NHCONR₅ R₇, NHSO₂ R₇, NHCO₂ R₇, SO₂ R₇, SO₂ NHR₇, NHCH₂ SR₇, NHCH₂ S(O)R₇, NHCH₂ SO₂ R₇, CN, NHCONH₂, SO₂ NH₂, N(SO₂ R₆, CH₂ NHCOR₇, CH₂ NHCONR₅ R₆, CH₂ NHSO₂ R₇, CH₂ NHCO₂ R₇, or OSO₂ R₇ radical which can be in the o, m, or p position on the aromatic ring,R'₁ represents a substituent which can be in various positions on the aromatic ring, selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, cycloalkyl, OH, SR₅, OR₅, chlorine, fluorine, bromine, and iodine or alternatively R' can be identical to R₁, Z represents C=O, C=S, SO₂, (CH₂)_(n), or --CO(CH₂)_(n) -- in which n is 1 to 5, inclusive, R₂ and R'₂, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical, or a phenyl, benzyl, cycloalkyl, or phenyl-alkyl radical which is optionally substituted by a substituent chosen from halogen alkyl, phenyl, carbonyl-derived C₁ -C₆ acyl, alkoxy, and alkylthio radicals, X represents CH₂ or O; the --C(R₂ R'₂)--X group can also represent a C═C double bond, R₃ represents a hydrogen atom, a linear or branched alkyl radical, or a phenyl, COR₇, CO₂, CO₂ R₇, CONHR₇, or SO₂ R₇ radical, R₄ represents a hydrogen, chlorine, fluorine, or bromine atom, or a linear or branched alkyl radical, R₅ and R₆, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl, or an arylalkyl radical selected from benzyl and phenethyl, R₇ represents a linear or branched alkyl radical having 1 to 5 carbon atoms inclusive, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, a heterocycle selected from thiophene and isoxazole, or arylalkyl selected from benzyl and phenethyl in which the aromatic ring may be variously substituted in various positions by methyl, ethyl, propyl or butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, thiol, OCH₃, OC₂ H₅ or OCH(Me)₂, SCH₃ or SC₂ H₅, chlorine, fluorine, bromine, or iodine, nitrile, COR₅, CO₂ R₅, NO₂, NR₅ R₆, NHSO₂ R₅, NHCO₂ R₅, NHCOR₅, NHCONR₅ R₆ or NHSO₂ NR₅ R₆, and its salts which are acceptable in therapeutic use.
 2. A compound selected from the group consisting of:2- 3-(2-Aminoethyl)-1-H-indol-5-yloxy!-1-(4-nitrophenyl)piperazin-1-yl!ethanone, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!1- 4-(aminophenyl)piperazin-1-yl!ethanone, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!acetamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!benzamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methanesulfonamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1-methylsulfonyl-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!methanesulfonamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!ethanesulfonamide, Thiophene-2-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide, Thiophene-2-{N- 4-(4-{2- 3-(2-aminoethyl)-1-(thiophene-2-sulfonyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide,
 3. 3. 5-Dimethylisoxazole-4-{N- 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5 -yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide,2- 3-(2-Aminoethyl)-1H -indol-5-yloxy!-1- 4-(4-N-{ethoxycarbonyl}aminophenyl)piperazin-1-yl!ethanone, 2,2,2-Trifluoroethane 4-(4-{2- 3-(2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!sulfonamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!isopropanesulfonamide, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-nitrophenyl)piperazin-1-yl)ethanone, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl)ethanethione, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(hydroxysunino)phenyl)piperazin-1-yl)ethanone, 2-{5- 4-(4-Nitrophenylpiperazine-1-sulfonylmethoxy!-1H-indol-3-yl}ethylamine, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!propane-1-one, 2- 3-(2-(Dimethylamino)ethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!ethanone, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(dimethylamino)phenyl)piperazin-1-yl!ethanone, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!benzenesulfonamide, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-methoxy-4-nitrophenyl)piperazin-1-yl!ethanone, 2-(5-{2- 4-(4-Nitrophenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethylamine, 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!prop-2-en-1-one, 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-nitrophenyl)piperazin-1-yl!propan-1-one, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!-4-nitrophenylsulfonamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2-phenylacetamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2-methoxybenzamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-2,2,2-trifluoroacetamide, 3- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-1,1-dimethylsulfonurea, Thiophene-2-carboxylic acid 4-(4-{2- 3-2-aminoethyl)-1H-indol-5-yloxy!acetyl}piperazin-1-yl)phenyl!amide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!phenylcarbamate, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-nitrobenzamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methylcarbamate, 3- 3-(2-Aminoethyl)-1H-indol-5-yl!-1- 4-(4-aminophenyl)-piperazin-1-yl!propan-1-one, N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!methanesulfonamide, N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!-N-dimethylsulfonylurea, N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!-4-nitrobenzenesulfonamide, N- 4-(4-{3- 3-(2-Aminoethyl)-1H-indol-5-yl!propionyl}-piperazin-1-yl)phenyl!benzamide, 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-ethyl}piperazin-1-yl)phenylamine, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl}piperazin-1-yl)phenyl!methanesulfonamide, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!methylcarbamate, 2-(5-{2- 4-(2-Methoxy-4-nitrophenyl)piperazin-1-yl)-ethoxy}-1-H-indol-3-yl)ethylamine, 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!ethyl!-piperazin-1-yl)benzonitrile, 2-(5-{2- 4-(4-(Aminomethyl)phenyl)piperazin-1-yl!ethoxy}-1H-indol-3-yl)ethyl!methylamine, 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-acetyl}piperazin-1-yl)benzonitrile, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(2-aminomethylphenyl)piperazin-1-yl!ethanone, N- 2- 4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzylmethanesulfonamide, N- 2-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl!benzenesulfonamide, 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzonitrile, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-(aminomethyl)phenyl)piperazin-1-yl!ethanone, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)benzyl!methane sulfonamide, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-amino-2-methoxyphenyl)piperazin-1-yl!ethanone, N- 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)-3-methoxyphenyl!methanesulfonamide, 2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitronaphth-1-yl)piperazin-1-yl!ethanone, 4-(4-{2- 3-(2-Aminoethyl)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl methanesulfonate, 6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!hexan-1-one, 6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-aminophenyl)piperazin-1-yl!hexan-1-one, N- 4-(4-{6 - 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanoyl}-piperazin-1-yl)phenyl!methanesulfonamide, N- 4-(4-{6- 3-(2-Aminoethyl)-1H-indol-5-yloxy!hexanol}-piperazin-1-yl)benzyl!benzenesulfonamide, 5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!pentan-1-one, 5- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(aminophenyl)-piperazin-1-yl!-pentan-1-one, 4- 3-(2-Aminoethyl)-1H-indol-5-yloxy!-1- 4-(4-nitrophenyl)piperazin-1-yl!butan-1-one, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-cyanophenylsulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-(trifluoromethane)phenylsulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-methoxyphenyl sulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-fluorophenylsulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-acetamidophenylsulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-aminophenyl sulfonamide, N- 4-(4-{2- 3-(2-Amino)-1H-indol-5-yloxy!acetyl}-piperazin-1-yl)phenyl!-4-(methanesulfonylamino)phenylsulfonamide, its salts, which are acceptable for therapeutic use.
 3. Pharmaceutical composition containing, as active ingredient an effective amount of a compound according to claim 1 in combination with an acceptable pharmaceutical vehicle.
 4. Pharmaceutical composition containing, as active ingredient an effective amount of a compound according to claim 2 in combination with an acceptable pharmaceutical vehicle.
 5. A method of treating anxiety, depression, migraine attacks, facial vascular pain, and chronic vascular cephalagias in a patient in need of such treatment, comprising the step of administering to the patient an effective amount of at least one compound according to claim
 1. 6. A method of treating anxiety, depression, migraine attacks, facial vascular pain, and chronic vascular cephalagias in a patient in need of such treatment, comprising the step of administering to the patient an effective amount of at least one compound according to claim
 2. 7. Process for the preparation of a compound of formula (I) ##STR97## in which: R₁ represents an NH₂, NO₂, NH--NH₂, NH--OH, NCOR₇ (OH), NR₅ R₆, NHCOR₇, NHCONR₅ R₇, NHSO₂ R₇, NHCO₂ R₇, SO₂ R₇, SO₂ NHR₇, NHCH₂ SR₇, NHCH₂ S(O)R₇, NHCH₂ SO₂ R₇, CN, NHCONH₂, SO₂ NH₂, N(SO₂ R₇)₂, CH₂ NR₅ R₆, CH₂ NHCOR₇, CH₂ NHCONR₅ R₆, CH₂ NHSO₂ R₇, CH₂ NHCO₇, or OSO₂ R₇ radical which can be in the o, m, or p position on the aromatic ring,R'₁ represents a substituent which can be in various positions on the aromatic ring, selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, benzyl, phenethyl, cycloalkyl, OH, SR₅, OR₅, chlorine, fluorine, bromine, and iodine, or alternatively R'₁ can be identical to R₁, Z represents C=O, C=S, SO₂, (CH₂)_(n), or --CO(CH₂)_(n) -- in which n is 1 to 5, inclusive, R₂ and R'₂, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical, or a phenyl, benzyl, cycloalkyl, or phenyl-alkyl radical which is optionally substituted by a substituent chosen from halogen, alkyl, phenyl, carbonyl-derived C₁ -C₆ acyl, alkoxy, and alkylthio radicals, X represents CH₂ or O; the --C(R₂ R'₂)--X group can also represent a C═C double bond, R₃ represents a hydrogen atom, a linear or branched alkyl radical, or a phenyl, COR₇, CO₂, CO₂ R₇, CONHR₇, or SO₂ R₇ radical, R₄ represents a hydrogen, chlorine, fluorine, or bromine atom, or a linear or branched alkyl radical, R₅ and R₆, which are identical or different, each represent a hydrogen atom, a linear or branched alkyl radical selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl, or an arylalkyl radical selected from benzyl and phenethyl, R₇ represents a linear or branched alkyl radical having 1 to 5 carbon atoms inclusive, trifluoromethyl, 2,2,2-trifluoroethyl, phenyl, a heterocycle selected from thiophene, isoxazole, or arylalkyl selected from benzyl and phenethyl in which the aromatic ring may be variously substituted in various positions by methyl, ethyl, propyl or butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, thiol, OCH₃, OC₂ H₅ or OCH(Me)₂, SCH₃ or SC₂ H₅, chlorine, fluorine, bromine, or iodine, nitrile, (COR₅), CO₂ R₅, NO₂, NR₅ R₆, NHSO₂ R₅, NHCO₂ R₅, NHCOR₅, NHCONR₅ R₆ or NHSO₂ NR₅ R₆,and R₆ represents a hydrogen, and its salts which are acceptable in therapeutic use, characterized in that a carbonate of formula ##STR98## in which all of the symbols have the same meaning as given in the foregoing and R₈ represents a ^(t) butyl or benzyl radical, is converted by acid hydrolysis when R₈ represents ^(t) Bu or by catalytic hydrogenation over palladium when R₈ represents a benzyl. 